“反向免疫学”与免疫功能基因的发现

人类基因组测序的结束为生命科学领域展开了全新的一章.尽管已经得到了人类基因组的序列,但是隐藏在DNA序列中的功能基因,它们之间的相互作用以及对整个机体的意义大部分有待发掘.近些年来形成的“反向生物学”为免疫功能基因的发现、功能的研究及其应用价值提供了一套全新的技术与思路.     

The Anthropology of Authenticity: Everyman His Own Anthropologist

Anthropology, the contributors to the recent volume Reinventing Anthropology tell us, is suffering from severe hardening of the intellectual arteries. In order for it to be revitalized, they say, the discipline must be de-professionalized and de-institutionalized, made more personal and existential. This involves a rejection of the pose of "objectivity" and "value-free" inquiry and an open admission of the inherently ideological nature of the discipline. In a word, anthropology will have to become politically and morally partisan. This essay explores some of the implications of the recommendations made by the reinventors of anthropology. The stance taken in Reinventing Anthropology, this paper contends, would not only undermine anthropology as a systematic field of inquiry but would also negate whatever "relevance" the discipline might have to the contemporary world.     

A passion for the science of the human genome

The complete sequencing of the human genome introduced a new knowledge base for decoding information structured in DNA sequence variation. My research is predicated on the supposition that the genome is the most sophisticated knowledge system known, as evidenced by the exquisite information it encodes on biochemical pathways and molecular processes underlying the biology of health and disease. Also, as a living legacy of human origins, migrations, adaptations, and identity, the genome communicates through the complexity of sequence variation expressed in population diversity. As a biomedical research scientist and academician, a question I am often asked is: “How is it that a black woman like you went to the University of Michigan for a PhD in Human Genetics?” As the ASCB 2012 E. E. Just Lecturer, I am honored and privileged to respond to this question in this essay on the science of the human genome and my career perspectives.

“Knowledge is power, but wisdom is supreme.”

     

Regeneration in the metazoans: why does it happen?

Why does regeneration occur? And why, when it manifests itself, does it do so in some but not all metazoan species? Hence, what are the permissive or inhibitory factors operating behind this phenomenon? When it comes to regeneration, many questions, such as these, remain unanswered. In fact, the problem of animal regeneration has withstood the probing of scientific inquiry for over 250 years and still awaits a satisfactory mechanistic explanation. In this essay, I will review the distribution and the modes of regeneration that are found in the different metazoan phyla. Also, I will re-examine ideas on its evolutionary origins, and discuss its possible relationship to both asexual reproduction and embryogenesis. This endeavor has two objectives. First, to bring forward an interpretation of regeneration which integrates evolutionary and developmental considerations into its discussion. And second, to suggest a comparative experimental approach to this problem that may bring us closer to understanding the molecular basis of this long-standing biological problem. BioEssays 22:578-590, 2000.     

How nontraditional model systems can save us

In this essay I would like to highlight how work in nontraditional model systems is an imperative for our society to prepare for problems we do not even know exist. I present examples of how discovery in nontraditional systems has been critical for fundamental advancement in cell biology. I also discuss how as a collective we might harvest both new questions and new solutions to old problems from the underexplored reservoir of diversity in the biosphere. With advancements in genomics, proteomics, and genome editing, it is now technically feasible for even a single research group to introduce a new model system. I aim here to inspire people to think beyond their familiar model systems and to press funding agencies to support the establishment of new model systems.My career as a biologist began in the orange groves and lake waters of central Florida. An unstructured childhood was spent learning to observe and wonder. Without realizing it at the time, my training began with the mantra, “Study nature, not books,” the familiar entreaty of Louis Agassiz, a founder of what would become the Marine Biological Lab (MBL) in Woods Hole, Massachusetts. In that humid air, listening to cicadas click, I subconsciously practiced asking basic questions about the structure of the natural world. I suspect many of us began our careers this way, even though we ended up thinking about systems of molecules from behind the black curtains of the microscope room, immersed in the frosty air of the cold room, or bathed in the glow of a computer screen. Before the grown-up challenges of funding, publishing, and progressing in a career, we easily marveled at the complexity and surprises of the living world. How can we recapture the joy that comes from curiosity-driven inquiry? This being an essay for the midcareer award, it seems appropriate to blend material for a midlife with a plan for how we as a cell biology community can identify big new questions. So instead of a fancy car, a new microscope, or a dangerous (professional) liaison, try developing a new model system as an outlet for your midlife crisis!Open in a separate windowAmy S. Gladfelter     

Gene duplication and fragmentation in the zebra finch major histocompatibility complex

Background

Due to its high polymorphism and importance for disease resistance, the major histocompatibility complex (MHC) has been an important focus of many vertebrate genome projects. Avian MHC organization is of particular interest because the chicken Gallus gallus, the avian species with the best characterized MHC, possesses a highly streamlined minimal essential MHC, which is linked to resistance against specific pathogens. It remains unclear the extent to which this organization describes the situation in other birds and whether it represents a derived or ancestral condition. The sequencing of the zebra finch Taeniopygia guttata genome, in combination with targeted bacterial artificial chromosome (BAC) sequencing, has allowed us to characterize an MHC from a highly divergent and diverse avian lineage, the passerines.

Results

The zebra finch MHC exhibits a complex structure and history involving gene duplication and fragmentation. The zebra finch MHC includes multiple Class I and Class II genes, some of which appear to be pseudogenes, and spans a much more extensive genomic region than the chicken MHC, as evidenced by the presence of MHC genes on each of seven BACs spanning 739 kb. Cytogenetic (FISH) evidence and the genome assembly itself place core MHC genes on as many as four chromosomes with TAP and Class I genes mapping to different chromosomes. MHC Class II regions are further characterized by high endogenous retroviral content. Lastly, we find strong evidence of selection acting on sites within passerine MHC Class I and Class II genes.

Conclusion

The zebra finch MHC differs markedly from that of the chicken, the only other bird species with a complete genome sequence. The apparent lack of synteny between TAP and the expressed MHC Class I locus is in fact reminiscent of a pattern seen in some mammalian lineages and may represent convergent evolution. Our analyses of the zebra finch MHC suggest a complex history involving chromosomal fission, gene duplication and translocation in the history of the MHC in birds, and highlight striking differences in MHC structure and organization among avian lineages.     

Purinergic Receptors,Past and Future (Closing Remarks)

Abstract

At the end of a symposium, it is useful to look back, both at the symposium itself and the developments that led up to the symposium. In this spirit, I thought it would be appropriate to tell the story of how I first became interested in purinergic receptors. I am recounting this story not because I believe that my audience has a burning interest in the history of my intellectual development, but rather because it illustrates the power of ideas.     

The viral era: New biotechnologies give humans an unprecedented control over Nature and require appropriate safeguards

New biotechnologies such as gene drives and engineered viruses herald a viral era that would give humans exceptional power over any organism at the level of the genotype. Subject Categories: Synthetic Biology & Biotechnology, S&S: Economics & Business, Ecology

We are entering a new phase in our relationship with nature: after mechanization, automation and digitalization, a new era of autonomous technical objects is dawning. The most advanced of these technologies are characterized by viral behaviour. The COVID‐19 pandemic has again aptly demonstrated the power of viral systems: not only because of the SARS‐CoV‐2 virus'' ability to jump into and rapidly spread among the human population while wreaking havoc with human societies, but also because some of the vaccines developed against the virus are themselves based on viruses. Both developments give us some ideas of the possible impact of new biotechnologies that aim to create artefacts with viral behaviour in order to shape and control our natural environment. In this essay, the focus is on the use of genetically engineered organisms and the genetic manipulation of wild species. This change has a more direct relationship to our natural environment than autonomous software artefacts such as computer apps or digital viruses that “live” in their artificial “ecosystems” of information‐processing devices. The development of artificial biological systems will therefore require new methods for monitoring and intervention given their potential to autonomously spread within natural ecosystems.     

A case for more curiosity-driven basic research

Having been selected to be among the exquisitely talented scientists who won the Sandra K. Masur Senior Leadership Award is a tremendous honor. I would like to take this opportunity to make the case for a conviction of mine that I think many will consider outdated. I am convinced that we need more curiosity-driven basic research aimed at understanding the principles governing life. The reasons are simple: 1) we need to learn more about the world around us; and 2) a robust and diverse basic research enterprise will bring ideas and approaches essential for developing new medicines and improving the lives of humankind.When I was a graduate student, curiosity-driven basic research ruled. Studying mating-type switching in budding yeast, for example, was exciting because it was an interesting problem: How can you make two different cells from a single cell in the absence of any external cues? We did not have to justify why it is important to study what many would now consider a baroque question. Scientists and funding agencies alike agreed that this was an exciting biological problem that needed to be solved. I am certain that all scientists of my generation can come up with similar examples.Open in a separate windowAngelika AmonSince the time I was a graduate student, the field of biological research has experienced a revolution. We can now determine the genetic makeup of every species in a week or so and have an unprecedented ability to manipulate any genome. This revolution has led to a sense that we understand the principles governing life and that it is now time to apply this knowledge to cure diseases and make the world a better place. While applying knowledge to improve lives and treat diseases is certainly a worthwhile endeavor, it is important to realize that we are far from having a mechanistic understanding of even the basic principles of biology. What the genomic revolution brought us are lists, some better than others. We now know how many coding genes define a given species and how many protein kinases, GTPases, and so forth there are in the various genomes we sequenced. This knowledge, however, does not even scratch the surface of understanding their function. When I browse the Saccharomyces cerevisiae genome database (my second-favorite website), I am still amazed how many genes there are that have not even been given a name.To me the most important achievement the new genome-sequencing and genome-editing technologies brought us is that nearly every organism can be a model organism now. We can study and manipulate the processes that most fascinate us in the organisms in which they occur, with the exception, of course, of humans. Thus, I believe that the golden era of basic biological research is not behind us but in front of us, and we need more people who will take advantage of the tools that have been developed in the past three decades. I am therefore hoping that many young people will chose a career in basic research and find an exciting question to study. The more of us there are, the more knowledge we will acquire, and the higher the likelihood we will discover something amazing and important. There is so much interesting biology out there that we should strive to understand. Some of my favorite unanswered questions are: What are the biological principles underlying symbiosis and how did it evolve? Why is sleep essential? Why do plants, despite an enormous regenerative potential, never die of cancer? Why do brown bears, despite inactivity, obesity, and high levels of cholesterol, exhibit no signs of atherosclerosis? How do sharks continuously produce teeth?One could, of course, argue that the knowledge we have accumulated over the past 50 years provides a reasonable framework, and it is now time to leave basic science and model organisms behind and focus on what matters—curing diseases, developing methods to produce energy, cleaning up the oceans, preventing global warming, building biological computers, designing organisms, or engineering whatever the current buzz is about. Like David Botstein, who eloquently discussed the importance of basic research in these pages in 2012 (Botstein, 2012 ), I believe that the notion that we already know enough is wrong and the current application-centric view of biology is misguided. Experience has taught us over and over that we cannot predict where the next important breakthrough will be emerge. Many of the discoveries that we consider groundbreaking and that have brought us new medicines or improved our lives in other ways are the result of curiosity-driven basic research. My favorite example is the discovery of penicillin. Alexander Fleming, through the careful study of his (contaminated) bacterial plates, enabled humankind to escape natural selection. More recent success stories such as new cures for hepatitis C, the human papillomavirus vaccine, the HIV-containment regimens, or treatments for BCR-ABL induced chronic myelogenous leukemia have also only been possible because of decades of basic research in model organisms that taught us the principles of life and enabled us to acquire the methodologies critical to develop these treatments. Although work from my own lab on the causes and consequences of chromosome mis-segregation in budding yeast has not led to the development of new treatments, it has taught us a lot about how an imbalanced karyotype, a hallmark of cancer, affects the physiology of cancer cells and creates vulnerabilities in cancer cells that could represent new therapeutic targets.These are but a few examples for why it is important that we scientists must dedicate ourselves to the pursuit of basic knowledge and why we as a society must make funding basic research a priority. Achieving the latter requires that we scientists tell the public about the importance of what we are doing and explain the potential implications of basic research for human health. At the same time, it will be important to manage expectations. We must explain that not every research project will lead to the development of new medicines and that we cannot predict where the next big breakthroughs will materialize. We must further make it clear that this means we have to fund a broad range of basic research at a healthy level. Perhaps a website that collects examples of how basic research has led to breakthroughs in medicine could serve as a showcase for such success stories, bringing the importance of what we do to the public.While conducting research to improve the lives of others is certainly a worthy motivation, it is not the main reason why I get up very early every morning to go to the lab. To me, gaining an understanding of a basic principle in the purest Faustian terms is what I find most rewarding and exciting. Designing and conducting experiments, pondering the results, and developing hypotheses as to how something may work is most exciting, the idea that I, or nowadays the people in my lab, may be (hopefully) the first to discover a new aspect of biology is the best feeling. It is these rare eureka moments, when you first realize how a process works or when you discover something that opens up a new research direction, that make up for all the woes and frustrations that come with being an experimental scientist in an expensive discipline.For me, having a career in curiosity-driven basic research has been immensely rewarding. It is my hope that basic research remains one of the pillars of the American scientific enterprise, attracting the brightest young minds for generations to come. We as a community can help to make this a reality by telling people what we do and highlighting the importance of our work to their lives.     

The jewels of our genome: the search for the genomic changes underlying the evolutionarily unique capacities of the human brain

The recent publication of the initial sequence and analysis of the chimp genome allows us, for the first time, to compare our genome with that of our closest living evolutionary relative. With more primate genome sequences being pursued, and with other genome-wide, cross-species comparative techniques emerging, we are entering an era in which we will be able to carry out genomic comparisons of unprecedented scope and detail. These studies should yield a bounty of new insights about the genes and genomic features that are unique to our species as well as those that are unique to other primate lineages, and may begin to causally link some of these to lineage-specific phenotypic characteristics. The most intriguing potential of these new approaches will be in the area of evolutionary neurogenomics and in the possibility that the key human lineage–specific (HLS) genomic changes that underlie the evolution of the human brain will be identified. Such new knowledge should provide fresh insights into neuronal development and higher cognitive function and dysfunction, and may possibly uncover biological mechanisms for information storage, analysis, and retrieval never previously seen.     

Towards the molecular dissection of fertilization signaling: Our functional genomic/proteomic strategies

Recent advances in DNA sequencing techniques and automated informatics has led to clarification of all genome sequence of some model organisms in a very short period. The demonstration of the first draft sequence of the human genome has prompted us to elaborate new approaches in biology, pharmacology and medicine. Such new research will focus on high throughput methods to function on collections of genes, and hopefully, on a genome-wide, quantitative modeling of the cell system as a whole. In this review article, we discuss the present status of "post genome sequencing" approaches in line with our strategies for understanding the molecular mechanism of fertilization and activation of development using the African clawed frog, Xenopus laevis, as a model system.     

Introduction to plant genomics]

The success in complete sequencing of "small" genomes and development of new technologies which sharply accelerate processes of cloning and sequencing made real an intensive development of plant genomics and complete sequencing of DNA of some species. It is assumed that the success in plant genomics will result in revolutionary changes in biotechnology and plant breeding. However, the enormous size of genomes (tens of billions bp), their extraordinary enrichment in repetitive sequences, and allopolyploidy (the presence in a nucleus of several related but not identical genomes) force us to think that only few "basic" will undergo complete sequencing, whereas the genome investigations in other species will follow principles of comparative genomics. By the present time, complete sequencing of the Arabidopsis genome (125 Mbp) is completed and that of the rice genome (about 430 Mbp) is close to its end. Studying other plant genomes, including those economically valuable, already began on the basis of these investigations. Peculiarities of plant genomes make extraordinarily important the knowledge on plant chromosomes which, in its turn, requires expansion of investigations in this direction and development of new chromosome technologies, including the DNA-sparing methods of high-resolution banding.     

Elusive locus of control in biological development: genetic versus developmental programs.

Taken as a composite, the meaning of the composite term "genetic program"-widely taken to suggest an explanation of biological development - simultaneously depends upon and underwrites the particular presumption that a "plan of procedure" for development is itself written in the sequence of nucleotide bases. Is this presumption correct? I want to argue that, at best, it must be said to be misleading, and at worst, simply false: To the extent that we may speak at all of a developmental program, or of a set of instructions for development, in contra-distinction to the data or resources for such a program, current research obliges us to acknowledge that these "instructions" are not written into the DNA itself (or at least, are not all written in the DNA), but rather are distributed throughout the fertilized egg. I will argue that the notion of genetic program depends upon, and sustains, a fundamental category error in which two independent distinctions, one between "genetic" and "epigenetic," and the other, between program and data, are pulled into mistaken alignment. The net effect of such alignment is to reinforce two outmoded associations: on the one hand, between "genetic" and active, and, on the other, between "epigenetic" and passive. J. Exp. Zool. (Mol. Dev. Evol.) 285:283-290, 1999.     

The roots of bioinformatics in theoretical biology

From the late 1980s onward, the term "bioinformatics" mostly has been used to refer to computational methods for comparative analysis of genome data. However, the term was originally more widely defined as the study of informatic processes in biotic systems. In this essay, I will trace this early history (from a personal point of view) and I will argue that the original meaning of the term is re-emerging.     

The microbial pan-genome

A decade after the beginning of the genomic era, the question of how genomics can describe a bacterial species has not been fully addressed. Experimental data have shown that in some species new genes are discovered even after sequencing the genomes of several strains. Mathematical modeling predicts that new genes will be discovered even after sequencing hundreds of genomes per species. Therefore, a bacterial species can be described by its pan-genome, which is composed of a "core genome" containing genes present in all strains, and a "dispensable genome" containing genes present in two or more strains and genes unique to single strains. Given that the number of unique genes is vast, the pan-genome of a bacterial species might be orders of magnitude larger than any single genome.     

The ascidian tadpole larva: comparative molecular development and genomics

Evolution is of interest not only to developmental biology but also to genetics and genomics. We are witnessing a new era in which evolution, development, genetics and genomics are merging to form a new discipline, a good example of which is the study of the origin and evolution of the chordates. Recent studies on the formation of the notochord and the dorsal neural tube in the increasingly famous Ciona intestinalis tadpole larva, and the availability of its draft genome, show how the combination of comparative molecular development and evolutionary genomics might help us to better understand our chordate ancestor.     

Teaching critical thinking in a developmental biology course at an American liberal arts college

We all expect our students to learn facts and concepts, but more importantly, we want them to learn how to evaluate new information from an educated and skeptical perspective; that is, we want them to become critical thinkers. For many of us who are scientists and teachers, critical thought is either intuitive or we learned it so long ago that it is not at all obvious how to pass on the skills to our students. Explicitly discussing the logic that underlies the experimental basis of developmental biology is an easy and very successful way to teach critical thinking skills. Here, I describe some simple changes to a lecture course that turn the practice of critical thinking into the centerpiece of the learning process. My starting point is the "Evidence and Antibodies" sidelight in Gilbert's Developmental Biology (2000), which I use as an introduction to the ideas of correlation, necessity and sufficiency, and to the kinds of experiments required to gather each type of evidence: observation ("show it"), loss of function ("block it") and gain of function ("move it"). Thereafter, every experiment can be understood quickly by the class and discussed intelligently with a common vocabulary. Both verbal and written reinforcement of these ideas dramatically improve the students' ability to evaluate new information. In particular, they are able to evaluate claims about cause and effect; they become experts at distinguishing between correlation and causation. Because the intellectual techniques are so powerful and the logic so satisfying, the students come to view the critical assessment of knowledge as a fun puzzle and the rigorous thinking behind formulating a question as an exciting challenge.     

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.     

小鼠母源因子对早期胚胎发育的影响

在脊椎动物中发育过程中,卵母细胞要经历MII期停滞、受精、早期胚胎发育的启动、胚胎基因组的转录激活、并指导完成个体的发育过程。同时,核移植过程中,分化的细胞核在去核的卵母细胞中能够重编程到胚胎早期的状态并能完成个体的发育过程。在这些发育过程中母源因子都发挥了极其的重要作用。在小鼠胚胎发育研究中发现,小鼠的基因组激活发生在2细胞期,这一时期标志着合子的发育由卵母细胞控制向胚胎控制的过渡,期间发生一系列复杂的生化过程。体外培养的小鼠的胚胎的发育阻断也易发生的2细胞时期。因此对卵母细胞及早期胚胎母源因子的研究,将有利于了解早期体外培养胚胎和克隆胚胎发育失败的原因,为提高体外培养和克隆胚胎发育的成功率提供理论的基础。     

后基因组——蛋白质组研究

１９９０年国际上开始了人类基因组研究。尽管目前只解出了约３％的序列,但功能基因组的研究已经开始,后基因组的时代已经到来。新时代的最终目的,是阐明基因组所表达的真正执行生命活动的全部蛋白质的表达规律和生物功能,也即蛋白质组研究。当前主要的研究手段为双向凝胶电泳、“双向”高效柱层析、质谱技术和生物信息学。蛋白质组研究,不仅是２１世纪整体细胞生物学新的最重要的内容,而且将为医药、农业和工业的革新提供崭新