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Scientists Share Common Interests at Human Biology Symposium
 More than 600 registrants attended the fourth Wisconsin Symposium on Human Biology at UW-Madison on May 22-25, 2006. This year scientists traveled from as far away as Shanghai and Novosibirsk (in the former Soviet republic of Siberia). Nearly half of the 44 invited speakers came from other institutions around the world, including Israel, Germany, England and Canada. William Dove, PhD, the Streisinger Professor of Experimental Biology at UW School of Medicine and Public Health (SMPH), was delighted with the global interest the symposia have garnered since he organized the first one in 1999.
Based at the McArdle Laboratory for Cancer Research, Dove assembled a cross-disciplinary committee of UW-Madison research leaders to organize the 2006 symposium. Support came from the Office of the Provost, the Graduate School, other schools, colleges, departments, centers and institutes across campus. Thanks to this support, and that of the Ellison Medical Foundation in Bethesda, Md., registration was free to members of academic institutions across Wisconsin.
Attendees were impressed with the symposium’s quality and scope.
“Over the past half century I have attended in excess of 100 meetings throughout the world. Your Wisconsin Symposium on Human Biology ranks among the very few that I found completely engrossing,” said John W. Drake, PhD, chief of the Laboratory of Molecular Genetics at the National Institute of Environmental Health Sciences and president of the International Genetics Federation. “The quality of the speakers was uniformly high in the sessions I attended and the vigorous following question periods revealed that many in the audience were similarly stimulated. The breadth of topics was striking, and it was particularly notable that you sampled best people from several countries outside of North America.”
Dove’s overview of the symposium follows.
The symposium opened with a plenary lecture by Michael Meaney, PhD, from McGill University in Montreal entitled Maternal Care, Genes, and the Development of Strategy. Through studies of fostering neonates between genetically distinct strains of the laboratory rat, Meaney evaluates the impact of early maternal influence on adult outcome and analyzes how this influence is maintained in the brain.
Meaney's lecture was moderated by Wisconsin's Richard Davidson, PhD, who on the following morning conducted a session on Emotion and the Brain. Davidson gained recent note, being honored by TIME magazine as one of the most influential people of 2006. There has been an explosion of research over the past decade on the neural circuitry underlying emotion and the interaction of emotion with cognition. This work joins findings from both animal and human studies. The human studies have been informed both by neuroimaging findings and by observations of specific emotional disturbances in patients with localized lesions. This work is providing a new more comprehensive understanding of human emotion: how emotion interacts with attention and memory, how emotion is regulated and how it can become dysregulated in psychopathology.
The Tuesday morning session featured the work of Elizabeth Phelps, PhD, one of the leaders in the new generation of affective neuroscientists who uses both lesion methods and neuroimaging to understand emotion-cognition interactions. Davidson reviewed recent findings on the neural substrates of emotion regulation and dysregulation in psychopathology.
Also on Tuesday morning, Wisconsin's Alan Attie, PhD, convened a session on Interactions Between Nutrition and Aging. Attie is investigating the genetics of insulin-resistant diabetes, both in mouse models and by human genetic association studies. A powerful synergy between molecular phenotyping and segregation in genetic crosses is permitting Attie and his colleagues to identify important regulatory loci in this biological system.
A central issue is the role of mitochondrial metabolism. In aging, mitochondrial function is disrupted. This is also true of diabetes. Vamsi Mootha, PhD, from the Broad Institute at MIT and Harvard, has studied this using some very clever approaches that combine bioinformatics with gene array and biochemical studies. Rudolph Leibel, PhD, from Columbia, is actively involved in a broad range of analyses of satiety, obesity and diabetes. He employs both mouse quantitative trait genetics and human genetic association studies. Eric Schadt, PhD, from Rosetta Inpharmatics and Merck, is performing a comprehensive analysis of the activity of the majority of the genes of the laboratory mouse in relation to inflammation pathways and metabolic traits. The logic by which these activities are organized is then deduced by the study of mice mutated in key regulatory genes.
One of the most powerful resources for the study of genetic determinants in humans is the population of Iceland, whose disease genetics has been nationalized under Decode Genetics. Through genetics, Schadt has been able to connect his studies over to susceptibility to obesity in the Icelandic population. Thus, a unifying theme in the session on Interactions Between Nutrition and Aging was the attempt to connect between animal studies and human populations using mammalian genetics and genomics. This theme was revisited in Wednesday afternoon’s Cancer Biology session moderated by Bill Sugden, PhD, of the SMPH. His colleague Michael Gould, PhD, is investigating genes that influence susceptibility to breast cancer, discovering them in the laboratory rat and then validating them in human populations.
The study of core relationships between metabolism, caloric restriction, hormones and aging is receiving new light from an invertebrate source – the powerful genetics of the soil nematode, C. elegans. Tuesday afternoon's closing plenary lecture on these studies was given by Cynthia Kenyon, PhD, from the University of California, San Francisco, moderated by Wisconsin's Judith Kimble, PhD.
Studies of human biology are becoming remarkably interdisciplinary. A strong component of this Fourth Wisconsin Symposium on Human Biology came from the College of Engineering. On Tuesday afternoon, Wisconsin's David Beebe, PhD, organized a session on Technology, Stem Cells and Regenerative Biology. Beebe discussed the fabrication of three-dimensional microenvironments by which to study cellular interactions. Wisconsin's Paul Bach-y-Rita, MD, discussed his development of electrotactile arrays by which individuals with vestibular disorders can substitute sensory reception through the tongue. Bach y Rita's studies have drawn international attention (see New York Times, November 30, 2004).
One of the most powerful technologies in the contemporary analytic repertoire is mass spectrometry. The growing power of this technology was seen at several points in the symposium, including the poster sessions that were on display throughout. In Beebe's session on technology, Charles Cantor, PhD, from Sequenom in San Diego, discussed the non-invasive detection of markers for fetal abnormalities and for cancer. In Wednesday morning's session on Systems Biology, convened by Wisconsin's John Yin (also from Engineering), PhD, and Ranga Sampath, PhD, from Ibis Biosciences in Carlsbad, California, described new mass spectrometric technologies for the rapid detection of microbial pathogens.
The Systems Biology session also introduced the emerging attempt to integrate elements previously studied as isolated processes and pathways. The long-horizon goal of systems biology is to understand how the genomes of organisms (including humans) interact with environmental resources and limitations to influence organismal development, reproduction and, ultimately, evolutionary fitness.
Nearer term goals aim to develop quantitative physical, chemical and biological descriptions of living organisms and their molecular processes. Such descriptions can begin to provide insight into how processes containing many components work in an integrated, coordinated and regulated manner. Pioneers in systems biology who spoke included Naama Barkai (Weizmann Institute, Israel), PhD, Erin O’Shea (Harvard), PhD, and Sampath (of Ibis Therapeutics). Yin discussed the systems biology of a “simple” biological process – viral growth. The efforts toward global synthesis were then evisited in Thursday afternoon’s final Plenary Lecture by Jeremy Nicholson, PhD, from Imperial College, London.
The diversity of cell types in the human is being traced back to key developmental nodes, or "stem cells.” The most widely known are those of the early embryo; embryonic stem cells, as first cultured from human embryos by Wisconsin's James Thomson, PhD, lie at the top of the developmental hierarchy. Closer to the current therapeutic attention are the more restricted stem cells for neural development and cancer.
In Beebe's Technology session, Wisconsin's Clive Svendsen, PhD, discussed the challenges of cell-based therapies for neurodegenerative diseases. In Wednesday afternoon's Cancer Biology session, John Dick, PhD, from Toronto and Wisconsin's Caroline Alexander, PhD, described research to identify the progenitors for leukemia and breast cancer. These “cancer stem cells” represent the ultimate target for durable therapy, although they may represent only a small fraction of the mass of a tumor.
The human species defines itself not only by the set of genes in the genome and the different forms each gene can take, but importantly by the ways that humans generate and transmit their cultures. The Symposium engaged this domain of inquiry in several of its sessions, beginning with Meaney’s opening plenary lecture discussed above.
The UW School of Education was strongly represented in a session Tuesday afternoon entitled Learning Science and the Science of Learning. Convened by Millard Susman, PhD, and moderated by Rayla Greenberg Temin, PhD--each among the most successful teachers of undergraduate science at UW-Madison--this session opened with a lecture by Mark McDaniel, PhD, from Washington University, St. Louis, who discussed basic research on learning techniques. Measuring memory transfer into long-term retention, McDaniel’s research investigates the impact of “active learning” and test-enhanced learning. He aims to discriminate between rote learning and the generation of an ability to abstract from the particular to the general. Three faculty from the UW School of Education--Sarah Laufer, PhD, Mitchell Nathan, PhD, and James Stewart, PhD-- discussed these issues:
- How can current knowledge derived from cognitive science be used to guide the practice of educators?
- We can turn to the field of educational psychology for models and for empirical studies that suggest ways in which biology education could be made more effective.
- What is learning?
- How is learning affected by students' prior knowledge?
- How can technology be used to promote learning?
- How can problem-solving and hands-on involvement in research be used to promote learning?
- And, for the general question of promoting science literacy, what is literacy anyway?
Issues in language, so central to our cultural transmission, arose in other guises in the sessions on Music and the Brain Wednesday afternoon and The Making of Homo sapiens on Thursday morning. In the latter session, Svante Paabo, PhD, from Leipzig, Germany, discussed one regulatory gene whose evolution has paralleled the acquisition of language in humans.
Wednesday morning brought a session on Psychosocial Factors and Biology, moderated by Carol Ryff, PhD, director of Wisconsin’s Institute on Aging. There is a growing literature focused on mechanisms linking psychological and social factors to health outcomes. Most of it examines negative psychosocial factors and their biological sequelae. Pathways from psychosocial adversity to cardiovascular disease, cancers at multiple sites, drug addiction and other functional disorders get the lion’s share of attention.
An important counterpoint to this work is the fact that many people exhibit resilience in the face of negative challenge and thereby manage to avoid, or significantly delay, negative pathways to disease. A further observation is that many people who have susceptibility genes for different diseases do not, in fact, proceed to disease status. Understanding these positive phenomena and their biological underpinnings is at the heart of a challenging research agenda focused on the promotion of good health. The purpose of this session was to present leading ideas about psychobiological mechanisms that may promote positive states of health and longer, disability-free life.
Dennis Charney, MD, from Mt. Sinai Hospital in New York builds from an extensive literature on neurochemical responses to acute stress and their links to psychopathology (depression, panic, anxiety) to address the neglected counterpoint question: what neurobiological mechanisms underlie resilient responses to stress? Andrew Steptoe, PhD, from University College, London, complements this formulation with an epidemiological perspective that examines the biological processes through which psychosocial factors influence disease risk. This literature has also been disproportionately focused on the negative – i.e., how adverse psychological and social characteristics increase disease risk measured in multiple systems (cardiovascular, neuroendocrine, immune). Steptoe’s recent work, however, focuses on the role of positive psychosocial factors and the roles they may play in reducing biological risk.
The point/counterpoint between causes of diseases and causes of health resonated through the three days of the symposium. So did the complementarity between Work Hard and Play Hard. Centered at the Memorial Union and State Historical Society, symposium participants had access to the Union Terrace, the Rathskeller and Tripp Commons for informal exchanges. Tuesday evening with the Mad City Jugglers, organized by Michael Newton, PhD, produced a Light Show on the Union Terrace. Wednesday evening, the Bach Dancing and Dynamite Society gave a ticketed concert in the new Playhouse of the Overture Center, playing music of Mozart, Steinfield and Brahms in honor of the 90th birth year of Wisconsin’s Professor James Crow, PhD, a lifelong conjoiner of science and music.
Wednesday afternoon’s symposium action included a session on Music and the Brain, convened and moderated by Wisconsin’s Jenny Saffran, PhD. This session highlighted exciting advances in the scientific study of music. How does the brain “hear” music? What happens when we hear music that is highly evocative; do those “chills” evoke a corresponding signal in the brain? Are there truly individuals who are tone deaf, and why? These scientists are learning a great deal about what makes music so special by investigating the neural bases of the psychology of music. Professor Saffran’s colleagues from Montreal, Isabelle Peretz, PhD, and Robert Zatorre, PhD, developed these issues, talking on When the Brain is Out of Tune, and Understanding the Brain Through Music and Perception, Imagery, and Emotion, respectively.
The exploration of sensory biology on Wednesday culminated in the Plenary Lecture by Peter Mombaerts, PhD, from Rockefeller University in New York. His lecture, moderated by Wisconsin’s Donata Oertel, PhD, described experiments on the rich olfactory sensory system of the laboratory mouse. How does each neuron select just one of the 1000-fold repertoire of olfactory receptor genes and then selectively project to a specific second-order neuron?
The final day of the symposium, Thursday, May 25, reached global levels of biological inquiry. In one morning session – The Making of Homo sapiens – convened by Wisconsin's John Hawks, PhD, and Sean Carroll, PhD. Pääbo, who as mentioned above also addressed language acquisition in another session, described work that compares the DNA sequences and activities of human versus chimpanzee genes and discussed evidence that suggests that genes expressed in the brain may have been particularly important during human evolution.
By contrast, Daniel Lieberman, PhD, from Harvard, discussed the selective importance of the capacity of humans as endurance athletes. One hypothesis is that human endurance, for both running and walking, is part of a suite of features selected during the transition from Australopithecus to Homo. While often assumed to be costly, it turns out that endurance running in arid environments is actually an economical and safe way for humans to hunt and scavenge, and would have provided a key competitive advantage to early humans before the invention of fire and hunting technology such as the bow and arrow.
As a third viewpoint on human evolution, Wisconsin's Karen Strier, PhD, discussed the importance of cultural behavior. This refers to the non-genetic transmission of practices ranging from tool-use to social customs such as distinct types of vocal communication, displays and ways of interacting with conspecifics. Cultural behavior begins with innovations that then require an element of learning to produce local, population-specific behavioral traditions. The connection of this topic to the Tuesday session on learning was intriguing.
Finally, Wisconsin’s Sean Carroll has been writing widely in the scientific and public literature on fundamental principles of evolution. He addressed several central questions, including: How can we identify the "smoking guns" of human genetic evolution from neutral ticks of the molecular evolutionary clock? Can the magnitude and rate of morphological evolution in hominids be explained as products of incremental developmental changes that are polygenic in nature?
The parallel session on Thursday morning addressed a global issue in contemporary human society: Race, Genetics, and Disease. Wisconsin's Joan Fujimura, PhD, convened three speakers from across the continent and from distinct disciplines: Marcus Feldman (Stanford), PhD, Troy Duster (NYU), PhD, and Richard Cooper (Loyola, Chicago) PhD. A key component of the efforts to understand variations in disease susceptibility is the notion of human population groups employed in the search for human genetic variations. However, in practice many researchers use common folk notions of race and ethnicity to designate their sample populations. Fierce debates are under way about using race/ethnic categories in genetic research.
The debates are about:
- the practicalities and politics of using genetic variation research, especially when race/ethnicity is a proxy for population, as a strategy to produce diagnostic or therapeutic methods in particular for common complex diseases such as heart disease, hypertension, asthma, and Type II diabetes;
- the political consequences of such research, given both the history of eugenics in the U.S. and the multiple discourses on populations, race and ethnicity in contemporary societies across the globe;
- the fact that some geneticists and genetic linkage analysts believe that new genetic technologies tell us that race is a biologically meaningful concept.
Duster has been speaking and writing against this move and on the problem of genetics research in the context of the history of eugenics in U.S. history. His concern centers on genetic research into behavioral differences between populations, especially statements about African Americans as being genetically more prone to violence. Cooper has used epidemiological evidence to argue against using race categories in genetic research into common complex diseases. Feldman has used worldwide human genetic variation data to produce a picture of world-wide human population structure that can be explained in terms of demographic history. These results inform discussions of the meaning of "race" and social classifications that affect healthcare decisions.
Thursday afternoon carried further the global issues affecting human biology. Teresa Compton, PhD, from both UW and Novartis Pharmaceuticals, convened a session on the Evolutionary Interactions Between H. sapiens and Microbes. Yoshihiro Kawaoka, PhD, a professor both in Tokyo and in Madison, is a leading expert on influenza epidemics. Kawaoka gave the opening talk in this session, reminding us of the "clear and present danger" constituted by the worldwide spread of avian flu, for which he now heads a research unit in Wisconsin.
Margaret McFall-Ngai, PhD, also from Wisconsin, gave a dynamic introduction to the biology of host/pathogen interactions. Compton then summarized her broad-ranging research program on the interactions between cytomegalovirus and the cells of its human host, giving insight into both natural resistance and acquired immunity. Finally, Eddie Holmes, PhD, from Pennsylvania State and Oxford universities, has recently published an informative review of the molecular evolution of some of the factors known to control natural resistance and adaptive immunity. He has also written a commentary on the 1918 influenza virus epidemic.
Thursday afternoon saw a parallel session on Circadian Biology, moderated by Ruth Benca, MD, PhD, from the SMPH’s Department of Psychiatry. Till Roenneberg, PhD, and colleagues in Munich, Germany, have collected data on sleeping patterns from more than 25,000 people in Germany and Switzerland. As part of their analysis, the researchers determined each person's "chronotype" by calculating the mid-point of their sleep--halfway between going to bed and waking up--on days when the subjects slept as late as they wanted. A surprising pattern emerged. Average chronotypes drift later and later during the teen years, but then begin to move steadily earlier after the age of 20. The researchers also saw differences between the sexes, with females having an earlier average chronotype than males until around age 50--consistent with menopause--when the correlation between age and chronotype seems to break down. This suggests that biological factors such as hormones have an important influence on the tendency to sleep late.
In addition to Benca, investigators interested in sleep/wake cycles included Giulio Tononi, MD, PhD, of the SMPH. Tononi's laboratory focuses on two main areas, consciousness and sleep. The work on consciousness has addressed the problem of how the activities of functionally specialized areas of the brain can be integrated to give rise to a unified conscious scene. Tononi’s work has led to the formulation of a testable proposal – the dynamic core hypothesis – about the neural substrates of consciousness. The work on sleep is carried out in collaboration with Chiara Cirelli, MD, PhD, using rat, mouse and fly models to understand the functions of sleep by focusing on the consequences of sleep and sleep deprivation at the cellular and molecular level. There are striking differences in the expression of certain genes between sleep and waking states. Based on a variety of behavioral, pharmacological, and molecular criteria, Cirelli and Tononi have discovered that sleep-like states are present in the fruit fly Drosophila. This finding opens the way to the genetic dissection of sleep using mutant screening and other powerful tools of genetic manipulation available in Drosophila. Terry Young, PhD, in the SMPH Department of Population Health Sciences, discussed her studies of relationships between sleep disorders and obesity.
The scientific agenda of the symposium closed with a plenary lecture by Jeremy Nicholson, PhD, from Imperial College, London, entitled Of Microbes, Men and Metabolism: Global Systems Biology Approaches to Modeling Human Disease. He discussed the challenge of delivering future personalized healthcare solutions and answering fundamental questions in molecular epidemiology, i.e., understanding the changes in the "Health of Nations" will require improved and deeper knowledge of human biology. One source of this knowledge is the collection of high technology "omics sciences" that give information at numerous levels of biomolecular organization. Humans and other advanced vertebrates have evolved as part of symbiotic associations with gut microbes. It has now been realized that the function of these "extended genomes" is critical in maintaining human health and disruptions of the microbial-mammalian metabolic axis may play a part in many diseases. In his lecture the concept of Global Systems Biology (understanding gene-environment interactions via an integrative multi-omics strategy) can be applied to study animal models of disease and human population variability.
The symposium closed after Nicholson's lecture with a banquet in the Great Hall of the Wisconsin Union. This banquet honored four distinguished Wisconsin faculty who remain active in different aspects of human biology: Rayla Greenberg Temin (Genetics and Undergraduate Teaching) PhD, James Crow (Human Genetics) PhD, Henry Lardy (Biochemistry) PhD, and Philip Farrell (Administration of the School of Medicine and Public Health), MD, PhD..
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