Development of molecular biology at the University of Wisconsin, Madison

Dramatic changes in the foundation of academic departments in our universities are uncommon. With the demonstration that DNA was the cellular source of genetic information, and that this information could be regulated, the field of molecular biology was born. Later, when scientists found that they could tinker with this information, the field matured. In an unusually rapid manner, molecular biology was integrated into the University of Wisconsin, Madison, in the late 1950s and early 1960s. This present article is a chronology of how it happened. What are the factors that made this transition possible in the University of Wisconsin? What lessons have we learned from this experience?     

Integrating evolutionary and molecular genetics of aging

Aging or senescence is an age-dependent decline in physiological function, demographically manifest as decreased survival and fecundity with increasing age. Since aging is disadvantageous it should not evolve by natural selection. So why do organisms age and die? In the 1940s and 1950s evolutionary geneticists resolved this paradox by positing that aging evolves because selection is inefficient at maintaining function late in life. By the 1980s and 1990s this evolutionary theory of aging had received firm empirical support, but little was known about the mechanisms of aging. Around the same time biologists began to apply the tools of molecular genetics to aging and successfully identified mutations that affect longevity. Today, the molecular genetics of aging is a burgeoning field, but progress in evolutionary genetics of aging has largely stalled. Here we argue that some of the most exciting and unresolved questions about aging require an integration of molecular and evolutionary approaches. Is aging a universal process? Why do species age at different rates? Are the mechanisms of aging conserved or lineage-specific? Are longevity genes identified in the laboratory under selection in natural populations? What is the genetic basis of plasticity in aging in response to environmental cues and is this plasticity adaptive? What are the mechanisms underlying trade-offs between early fitness traits and life span? To answer these questions evolutionary biologists must adopt the tools of molecular biology, while molecular biologists must put their experiments into an evolutionary framework. The time is ripe for a synthesis of molecular biogerontology and the evolutionary biology of aging.     

Timeline: Neurospora: a model of model microbes

In the 1940s, studies with Neurospora pioneered the use of microorganisms in genetic analysis and provided the foundations for biochemical genetics and molecular biology. What has happened since this orange mould was used to show that genes control metabolic reactions? How did it come to be the fungal counterpart of Drosophila? We describe its continued use during the heyday of research with Escherichia coli and yeast, and its emergence as a biological model for higher fungi.     

Overview: Protein palmitoylation in the nervous system: Current views and unsolved problems

Palmitoylation refers to a dynamic post-translational modification of proteins involving the covalent attachment of long-chain fatty acids to the side chains of cysteine, threonine or serine residues. In recent years, palmitoylation has been identified as a widespread modification of both viral and cellular proteins. Because of its dynamic nature, protein palmitoylation, like phosphorylation, appears to have a crucial role in the functioning of the nervous system. Several important questions regarding the post-translational acylation of cysteine residues in proteins are briefly discussed: (a) What are the molecular mechanisms involved in dynamic acylation? (b) What are the determinants of the fatty acid specificity and the structural requirements of the acceptor proteins? (c) What are the physiological signals regulating this type of protein modification, and (d) What is the biological role(s) of this reaction with respect to the functioning of specific nervous system proteins? We also present the current experimental obstacles that have to be overcome to fully understand the biology of this dynamic modification.     

Structure-function relationships in plant phenylpropanoid biosynthesis

Plants, as sessile organisms, evolve and exploit metabolic systems to create a rich repertoire of complex natural products that hold adaptive significance for their survival in challenging ecological niches on earth. As an experimental tool set, structural biology provides a high-resolution means to uncover detailed information about the structure-function relationships of metabolic enzymes at the atomic level. Together with genomic and biochemical approaches and an appreciation of molecular evolution, structural enzymology holds great promise for addressing a number of questions relating to secondary or, more appropriately, specialized metabolism. Why is secondary metabolism so adaptable? How are reactivity, regio-chemistry and stereo-chemistry steered during the multi-step conversion of substrates into products? What are the vestigial structural and mechanistic traits that remain in biosynthetic enzymes during the diversification of substrate and product selectivity? What does the catalytic landscape look like as an enzyme family traverses all possible lineages en route to the acquisition of new substrate and/or product specificities? And how can one rationally engineer biosynthesis using the unique perspectives of evolution and structural biology to create novel chemicals for human use?     

Making restoration history: reconsidering Aldo Leopold's Arboretum dedication speeches

Scholarship surrounding Aldo Leopold's involvement in the University of Wisconsin Arboretum in Madison, Wisconsin, has often pointed to Leopold's 1934 dedication speech as a significant historical artifact. While reflecting both Arboretum history and the development of Leopold's thought and influence, the speech may also have been the first publically articulated rationale for ecological restoration in the modern era. This scholarly personal essay describes my 50‐year relationship with both Leopold and the Arboretum, and my recent research that offers a new historical interpretation of Leopold's speech. Two versions of the speech exist; tensions between them have been discussed in at least two professional journals. What I learned from examining the archival record indicates that we really don't know for sure what Leopold said that June morning of 1934. What we can be sure of, however, is that the dedication speech usually attributed to Leopold, by such able scholars as Curt Meine and Baird Callicott, was not the one Leopold actually delivered. What many historians continue to refer to as Aldo Leopold's 1934 Arboretum dedication speech was actually written for another Wisconsin audience. As I explored this mystery, I rediscovered Leopold's passion for ecological restoration and his commitment to educate a diverse, Depression‐era public about its goals and purposes. For Leopold, restoration involved not only the expression of social and ecological values, but also public critique of the destructive social forces that make restoration necessary. Embodying social critique and ecological science, Leopold continues to model for us personal and professional roles as public ecological citizens dedicated to land.     

Evaluation of the rates of biological processes from tracer kinetic data. IV. Digital simulation of nucleic acid metabolism in bacteria

A flexible computer program was set up to simulate the kinetics of the amounts of radioactivity and the amounts of substance in various classes of nucleic acids for a generalized biological system. This program works by transferring numbers from registers to other registers corresponding to the amounts of isotope label or the amount of substance moving from one pool or compartment to another for each successive time interval. It is practical to choose the time interval small enough so that the same results are accurately obtained with this type of computation as with the analytical solution for the most realistic and complicated case previously formulated. Much more complicated situations now can be treated with this recursion program and questions of relevance to current molecular biology can be answered. The questions treated in this paper are directed to enteric microorganisms and are as follows. (1) What are the conditions under which a short pulse reflects net synthesis and what are the conditions where it reflects total synthesis? (2) What are the conditions that measurement of intermediate pool specific activity can yield information about the turnover and concentration of unstable macromolecules in the system? (3) How prolonged can a pulse be and still label the species of RNA substantially in proportion to their rates of synthesis? (4) What are the amounts and rates of synthesis and degradation of ribosomal precursors best fitting data in the literature?     

基因流存在条件下的物种形成研究述评:生殖隔离机制进化

物种形成过程是生物多样性形成的基础, 长期以来一直是进化生物学的中心议题之一。传统的异域物种形成理论认为, 地理隔离是物种分化的主要决定因子, 物种形成只有在种群之间存在地理隔离的情况下才能发生。近年来, 随着种群基因组学的发展和溯祖理论分析方法的完善, 种群间存在基因流情况下的物种形成成为进化生物学领域新的研究焦点。物种形成过程中是否有基因流的发生?基因流如何影响物种的形成与分化?基因流存在条件下物种形成的生殖隔离机制是什么?根据已发表的相关文献资料, 作者综述了当前物种形成研究中基因流的时间和空间分布模式、基因流对物种分化的影响以及生殖隔离机制形成等问题, 指出基因流存在条件下的物种形成可能是自然界普遍发生的一种模式。     

Bioelectricity and epimorphic regeneration

All cells have electric potentials across their membranes, but is there really compelling evidence to think that such potentials are used as instructional cues in developmental biology? Numerous reports indicate that, in fact, steady, weak bioelectric fields are observed throughout biology and function during diverse biological processes, including development. Bioelectric fields, generated upon amputation, are also likely to play a key role during vertebrate regeneration by providing the instructive cues needed to direct migrating cells to form a wound epithelium, a structure unique to regenerating animals. However, mechanistic insight is still sorely lacking in the field. What are the genes required for bioelectric‐dependent cell migration during regeneration? The power of genetics combined with the use of zebrafish offers the best opportunity for unbiased identification of the molecular players in bioelectricity. BioEssays 29:1133–1137, 2007. © 2007 Wiley Periodicals, Inc.     

An RNA Phage Lab: MS2 in Walter Fiers’ Laboratory of Molecular Biology in Ghent, from Genetic Code to Gene and Genome, 1963–1976

The importance of viruses as model organisms is well-established in molecular biology and Max Delbrück’s phage group set standards in the DNA phage field. In this paper, I argue that RNA phages, discovered in the 1960s, were also instrumental in the making of molecular biology. As part of experimental systems, RNA phages stood for messenger RNA (mRNA), genes and genome. RNA was thought to mediate information transfers between DNA and proteins. Furthermore, RNA was more manageable at the bench than DNA due to the availability of specific RNases, enzymes used as chemical tools to analyse RNA. Finally, RNA phages provided scientists with a pure source of mRNA to investigate the genetic code, genes and even a genome sequence. This paper focuses on Walter Fiers’ laboratory at Ghent University (Belgium) and their work on the RNA phage MS2. When setting up his Laboratory of Molecular Biology, Fiers planned a comprehensive study of the virus with a strong emphasis on the issue of structure. In his lab, RNA sequencing, now a little-known technique, evolved gradually from a means to solve the genetic code, to a tool for completing the first genome sequence. Thus, I follow the research pathway of Fiers and his ‘RNA phage lab’ with their evolving experimental system from 1960 to the late 1970s. This study illuminates two decisive shifts in post-war biology: the emergence of molecular biology as a discipline in the 1960s in Europe and of genomics in the 1990s.     

Centrosome and spindle pole body dynamics. Review and abstracts of the EMBO/EMBL Conference on Centrosomes and Spindle Pole Bodies,Heidelberg, September 13-17, 2002

Five years after the first meeting held on Centrosomes and Spindle Pole Bodies, a second meeting was organized by Tano Gonzalez, Eric Karsenti, Kip Sluder, and Mark Winey in Heidelberg, Germany. Sponsored by the gracious European community (EMBO/EMBL), the meeting was both spectacular and exhausting. The wealth of information delivered, the plethora of model systems and unique approaches described, and the free exchange of information by a cooperative and excited community of scientists overwhelmed all participants. Even the best prepared scholars could not have anticipated the avalanche of data and insights that poured from the presentations from beginning to end. Daily posters by young and senior scientists added dimension to round out the well-planned series of presentations. The meeting began with opening remarks by Eric Karsenti and Michel Bornens who reminded participants of the historical questions of the field. Where does the centrosome come from? What are the mechanisms that control centrosome assembly and duplication? How is duplication coordinated with the cell cycle? Why do some cells have centrosomes, while others do not? What are the components of the centrosome? Does the centrosome play an important role in disease?     

物种形成基因及其功能

什么是物种?新物种是如何形成的？这些问题是生命科学研究的重大问题.物种的形成是在生殖隔离的基础上某些新的生物学性状的形成和保留,是生物进化的最基本过程,其实质是基因结构突变的积累与功能的分化. 地理隔离使群体中的基因不能交流,基因突变也会影响个体间交配趣向,从而造成交配隔离或者交配后杂合体的基因组不亲和、杂交不育甚至杂交不活,使不同的群体逐渐分化为新物种. 随着分子生物学与基因组学的飞速发展,进化生物学家已经发现一些与物种形成有关的基因-物种形成基因（speciation genes）,鉴定并了解这些基因的功能,不仅能使我们在分子水平上理解新物种形成的实质和规律、而且对于我们突破种间屏障进行远缘杂交育种也有重要的理论指导意义.本文综述了目前对几个物种形成基因及其功能的研究进展,为该领域的进一步研究提供资料.     

From Types to Populations: A Century of Race, Physical Anthropology, and the American Anthropological Association

In the 1960s, U.S. physical anthropology underwent a period of introspection that marked a change from the old physical anthropology that was largely race based to the new physical anthropology, espoused by Washburn and others for over a decade, which incorporated the evolutionary biology of the modern synthesis. What actually changed? What elements of the race concept have been rejected, and what elements have persisted, influencing physical anthropology today? In this article, I examine both the scientific and social influences on physical anthropology that caused changes in the race concept, in particular the influence of the American Anthropological Association. The race concept is complicated but entails three attributes: essentialism, cladistic thinking, and biological determinism. These attributes have not all been discarded; while biological determinism and its social implications have been questioned since the inception of the field, essentialism and the concomitant rendering of populations as clades persists as a legacy of the race concept. [Keywords: race, essentialism, physical anthropology]     

The role of textbooks in communicating developmental biology

Writing a textbook that synthesized the field from the perspectives of embryology, genetics, cell biology and molecular biology was a challenge. Because this field evolves so rapidly, a textbook can only lay the basic foundation for understanding new information and provide the framework that helps scholars place new information into context throughout their career. In this essay, I propose that an international college of specialists be established to provide authoritative online updates on developmental biology topics as a service to students and the professional developmental biology community.     

Defects in the prostaglandin system--what is known?

The central role of prostaglandins as local mediators is well accepted. Molecular biology and in particular knock-out mice models teach us a lot on mechanisms and eventual biological consequences. Despite the broad basic knowledge available, human data on defects in the prostaglandin system are extremely rare. Why? Don't we search for them? Are they of clinical relevance? What is their prevalence, the outcome? How to treat, if possible? For this purpose we are planning a platform and databank to improve knowledge, pool information and allow exchange of probes. All interested people are invited to join.     

Linking stemness with colorectal cancer initiation,progression, and therapy

The discovery of cancer stem cells caused a paradigm shift in the concepts of origin and development of colorectal cancer. Several unresolved questions remain in this field though. Are colorectal cancer stem cells the cause or an effect of the disease? How do cancer stem cells assist in colorectal tumor dissemination to distant organs? What are the molecular or environmental factors affecting the roles of these cells in colorectal cancer? Through this review, we investigate the key findings until now and attempt to elucidate the origins, physical properties, microenvironmental niches, as well as the molecular signaling network that support the existence, self-renewal, plasticity, quiescence, and the overall maintenance of cancer stem cells in colorectal cancer. Increasing data show that the cancer stem cells play a crucial role not only in the establishment of the primary colorectal tumor but also in the distant spread of the disease. Hence, we will also look at the mechanisms adopted by cancer stem cells to influence the development of metastasis and evade therapeutic targeting and its role in the overall disease prognosis. Finally, we will illustrate the importance of understanding the biology of these cells to develop improved clinical strategies to tackle colorectal cancer.     

In search of the "hair cycle clock": a guided tour

The hair follicle, a unique characteristic of mammals, represents a stem cell-rich, prototypic neuroectodermal-mesodermal interaction system. This factory for pigmented epithelial fibers is unique in that it is the only organ in the mammalian body which, for its entire lifetime, undergoes cyclic transformations from stages of rapid growth (anagen) to apoptosis-driven regression (catagen) and back to anagen, via an interspersed period of relative quiescence (telogen). While it is undisputed that the biological "clock" that drives hair follicle cycling resides in the hair follicle itself, the molecular nature of the underlying oscillator system remains to be clarified. To meet this challenge is of profound general interest, since numerous key problems of modern biology can be studied exemplarily in this versatile model system. It is also clinically important, since the vast majority of patients with hair growth disorders suffers from an undesired alteration of hair follicle cycling. Here, we sketch basic background information and key concepts that one needs to keep in mind when exploring the enigmatic "hair cycle clock"(HCC), and summarize competing models of the HCC. We invite the reader on a very subjective guided tour, which focuses on our own trials, errors, and findings toward the distant goal of unravelling one of the most fascinating mysteries of biology: Why does the hair follicle cycle at all? How does it do it? What are the key players in the underlying molecular controls? Attempting to offer at least some meaningful answers, we share our prejudices and perspectives, and define crucial open questions.     

Neurotransmitter release at central synapses

Our understanding of synaptic transmission has grown dramatically during the 15 years since the first issue of Neuron was published, a growth rate expected from the rapid progress in modern biology. As in all of biology, new techniques have led to major advances in the cell and molecular biology of synapses, and the subject has evolved in ways (like the production of genetically engineered mice) that could not even be imagined 15 years ago. My plan for this review is to summarize what we knew about neurotransmitter release when Neuron first appeared and what we recognized we did not know, and then to describe how our views have changed in the intervening decade and a half. Some things we knew about synapses--"knew" in the sense that the field had reached a consensus--are no longer accepted, but for the most part, impressive advances have led to a new consensus on many issues. What I find fascinating is that in certain ways nothing has changed--many of the old arguments persist or recur in a different guise--but in other ways the field would be unrecognizable to a neurobiologist time-transported from 1988 to 2003.