A Plethora of Trees in the Cytoplasm

1999 Cell  
In the best articles, generally those dealing with basic Chromosome Puffs research, the combination of depth and accessibility is impressive. One on Hox genes introduces the notion of The Science Times Book of Genetics a conserved body plan among species, illustrating the Edited by Nicholas Wade point with the fauna of Star Trek, and continues with New York: The Lyons Press (1999). 256 pp. an explanation of the relationships between Hox gene $25.00 arrangements and Hox gene activities.
more » ... s from scientists involved in the research, and a terrific graphic, explain the singularity and compelling nature of this rela-Readers of Cell do not rely upon the New York Times tionship. The article's treatment of a novel model for Science Times section to keep up with the latest discovcoordination of Hox gene function makes clear that it eries in biology, but apparently other people do. Every is only theory, as yet unsupported by evidence, while Tuesday, the Times publishes a section on science and managing to demonstrate its power in clear and effective health. Most weeks, the coverage features new contrilanguage. butions to biomedical research, and especially modern Most of the articles feature multiple quotes from scigenetics, the origins of disease, gene therapy, genoentists who participated in the work, or who know it. In mics, and development. The weekly, prominent commitsome instances, the scientist is objective and underment of that much space in our most nearly national stated, portraying honest uncertainty in a fashion that newspaper makes the Science Times the most imporsupports the credibility of the scientific enterprise. A tant print source, and probably the most respected model of candor is the comment from a leading investisource, of news about biology. It is not coincidence gator in the olfaction field: "It's really not clear what is that basic biomedical science and its applications now going on yet." In other cases, the quotes show enthusireceive this level of attention. The public is aware of asm and inject a human element into research. That's biological research more than ever before, because biounderstandable, but often the authors have somehow medicine is moving closer to what people want from it, elicited and then selected for publication some unfairly and in some instances to what they fear from it. Biolosilly and unhelpful remarks. A surprisingly large fraction gists in turn have a serious stake in a well-informed of quotes from scientists begin with the word "Wow." public in order to sustain support, to retain biomedical And it isn't clear whether calling a particularly striking research's privileged budgetary status among discreresult (the characterization of the eyeless gene) "Franktionary programs, and to assuage those fears. ensteinian science at its best" will make the work more This collection presents 43 articles about modern geor less attractive to Times readers. netics that appeared in the Science Times over the last Inevitably, these articles deal not only with science several years, representing the work of four writers. Their but also with the expectations of what science can offer. subjects range broadly: modern approaches to the natu-For those discoveries that have potential medical appliral history of our species, molecular approaches to clascations, the weight of those expectations increases. The sical questions in development, new approaches to huworst thing these articles can do for the reader and for man diseases and aging. The subjects of most articles science is to create unrealistic hopes for imminent cures are well chosen to present exciting science at the foreto fatal diseases. In some instances, that risk is mitigated front of what is understood. Practicing biologists may by balance within the story. For example, in the course be impressed that the authors chose such complex subof a highly optimistic description of a gene discovery jects, and it is interesting to see how well new research "that offers a new way of preventing many cases of results travel from scientific presentation to popular precolon cancer," the author also offers Francis Collins's sentation. More important than those considerations, caution against overstating the risk associated with these particular mutations. the book is to be taken seriously because it is shows how a significant segment of the public-consumers, But too often, the stories appear without the caveats. The presentation of a possible therapy for glioblastoma taxpayers, patients-gets its contemporary education in biology. is particularly troublesome. It describes a single surviving patient in a gene therapy protocol, unusual but not The results are uneven. Some of the articles are lucid and crisp analyses of the importance of the science, entirely unprecedented. The investigator cautiously makes little claim of efficacy, but the article notes that presenting results in both contemporary and historical contexts that illuminate the questions and potential an-the sponsoring company has proceeded with tests in a small group of patients. That was eight months before swers. They discuss openly the scientific and public controversies that accompany the new findings, and the article was written, and more than three years before this book was published. In the case of the article, there appropriately foresee controversies to come. In other articles, however, the science is sacrificed to simplicity should have been a follow-up story; and when the article was reprinted in the book, there should have been a and hype, selling the prospects of the work in a way that risks creation of false expectations. Worse, some footnote. There are people waiting for this news. In several other stories, the other side, the side of caution, is articles ignore the standards of both science and journalism, and, in fact, do damage. just missing. "[I]t is probably only a matter of time before Cell 692 some of these defects can be corrected," says the Intro-as an example, consult the weekly Science and Technolduction, referring specifically to Huntington's disease ogy section of The Economist. and hereditary forms of cancer but presaging several articles in the book. That's very likely true, of course, Frank Solomon but how much time? With what obstacles? Department of Biology Some of the articles, to their credit, note the way our Center for Cancer Research society and economy affect science, and vice versa. For Massachusetts Institute of Technology example, the dilemma presented by the development Cambridge, Massachusetts 02139 of a genetic test for a condition that has no cure is raised in appropriate contexts. However, the influence of the biotechnology and pharmaceutical industries and their profit motives on the direction and pace of research is treated only occasionally. One article deals with the The Cell: The Development promises and risks of gene therapy. In it, N.I.H. Director of an Idea Book Reviews 693 the rise of Prussian nationalism after the defeat at Jena candidates for the role of victim of historical injustice, though how far this was due merely to his nationalism is reflected in the German treatment of French rivals, and vice versa. British historians in turn have been prone and how far it was because few could read his articles remains unclear. His institute in Breslau has been called to exaggerate the achievements of Robert Hooke, who contributed so much experimental work during the early "the cradle of histology." In the gradual development during the 1830s and years of the Royal Society of London. However, it is clear from Harris's book that by the 19th century, the 1840s of the understanding of the ubiquity of cell propagation by binary fission, and of the complexity of the driving force behind the development of the cell theory was from scientists operating in the German sphere cell, Prof. Harris urges that the role of Mü ller, Schleiden, and Schwann has been greatly exaggerated, not only of influence. Harris provides an extensive selection of quotations in the original language, a perusal of which at the expense of Purkyne "who argued that all solid animal tissues were composed essentially of cells and shows that a knowledge of German is essential for understanding the primary literature of this history. fibres, and who referred specifically, to the homology between animal and plant cells" (p.93), but also to the Harris begins his discussions with Galileo, a committed atomist, who by 1614 had developed a microscope detriment of the later work of Franz Unger, who worked in Graz and Vienna, and of Ferdinand Cohn who worked that he used to examine the cuticle of the fly. By 1660, Hooke had begun development of compound micro-in Breslau all his academic life. During the same period "The demonstration that the egg was itself a cell and scope with which he saw microscopic cavities in cork, probably the cell walls, and coined the term cellulae-that it begat daughter cells by binary fission marked a decisive step in the growth of what later became the possibly from the latin cella, meaning room or cubicle. Six years after the appearance of Hooke's Micrographia science of genetics" (p. 127). Harris writes "If there was one individual who, above in 1665, manuscripts from Nehemiah Grew and Marcello Malpighi laid the basis for the modern understanding of any other, was responsible for bringing order into the confusion that shrouded the origin of animal cells, it was the microanatomy of plants, while Malpighi also established a systematic methodology for the study of animal Robert Remak. It was not acknowledged in his lifetime . . . nor is it adequately recognized even now" (p. tissue. By the early 18th century and the work of van Leeuwenhoek, it was clear that plant tissue was com-128). Reading quotations from Remak, it is hard to disagree with Harris. As in the case of Purkyne, the reasons posed of microcavities but their nature was unclear. During the 18th century there was a great deal of micro-were partly nationalistic: Remak was born in Posen and was an orthodox Jew. "By 1852 Remak had come to scopic study and much discussion about the basic components of tissue. By the end of the 18th century, most the view that the only form of cell multiplication to be found in the animal body was multiplication by means botanists agreed with the idea that all plants were composed of cells. During the early 19th century the common of binary fission", which he set out in a paper entitled "Ueber extracellulare Entstehung thierischer Zellen and properties of plant cells were investigated using greatly improved microscopes, and Prof. Harris gives a knowl-ü ber Vermehrung derselben durch Theilung (On the Extracellular Formation of Animal Cells and Their Multipli-edgeable and balanced discussion of the many contributions, as well as of the controversies in estimating cation by Division)" (p. 130). However, "the rapid and widespread acceptance of Remak's ideas was not due these contributions. In particular he threads his way through the research of the 17th and 18th centuries with to the meticulous observations of Robert Remak, but to the propagandist skill of Rudolf Virchow (p. 135)," and remarkable clarity through what is a complex and manysided subject. He lists (p. 38) four topics still under con-particularly to the success of his celebrated book Die Cellularpathologie. sideration at the beginning of the 19th century: (1) How are new cells formed? (2) Do cells communicate with During the third quarter of the 19th century there was a gradual development of understanding of the division each other, and if so how? (3) What do cells contain? (4) Are all tissues comprised of modified cells? of the cell nucleus, and also of the indispensability of the cell membrane. Then "With the work of Balbiani and The study of these issues appears to mimic to some extent the recent studies on the molecular basis of cell van Benenden we move away from debate about the mechanism of nuclear division to a precise delineation physiology and development in the second half of the 20th century. Just as investigators studying the molecu-of chromosomes and what they do during division of the cell. . . . By 1876, Balbiani's observations had lar basis of development did not initially equate the development of a fruit fly with that of a mouse, so the reached an altogether different level of precision. Balbiani saw essentially all the stages of mitosis and noted investigators of the 18th and early 19th century did not equate the cells of plants with those of animals: the that, when the cell divided, the nucleus dissolved into a collection of 'bâ tonnets é troits' (narrow little rods)" (p. unicellular organisms first seen by Leeuwenhoek or the red blood corpuscles studied by Swammerdam, Leeu-153). Moreover, it was clear the "bâ tonnets" were not identical. "The principal impetus for the transition from wenhoek, and Malpighi, the first animal cells to be visualized. purely descriptive to analytical chromosome cytology was, however, the accumulation of data concerning the The clear establishment of the separate cellular nucleus, and also of the basic similarity of structure of fertilization and early development of the egg." The properties of chromosomes and their role in heredity animal and plant cells, developed after about 1825 and was the work of a number of people. One of the major were beginning to be elucidated, and early in the present century they were related to Mendel's heredity factors. figures was Jan Evangelist Purkyne, a Czech nationalist who wrote largely in Czech, though educated in the After this time the problems being considered in the biology of the cell bear a remarkable family resemblance main Germanic tradition. He is another of Prof. Harris's Cell 694 to the problems occupying cellular biologists today, a wider readership. There are bigger and better reviews even though modern knowledge and technical rein the literature-this is no Annual Review-and alsources are incomparably greater. though the "bound papers" format does not provide for Prof. Harris has written a clear, erudite, and balanced much cohesion within the book, it would be a useful history of the development of knowledge of the cell up addition to an institutional library. to the beginning of the 20th century that will appeal In A Means to an End, William Clark illustrates the to all biologists with an interest in the origins of their opposite approach, that of using a single author to cover subject. the entire field. The potential hazards are obvious, since no single author could ever hope to have direct experience in all the topics one would need to cover. Clark's * EMBL thesis seems to be that all aging comes down to senes-Meyerhofstrasse 1 cence at the cellular level, and that ultimately all "cellular Heidelberg 69117 senescence"-be it in yeast, paramecium, neurons, or Germany dividing fibroblasts-will reveal the same underlying † Department of Computer Science cause. Although such a reductionist approach would Exeter University certainly make the field easier to deal with, so it must Exeter EX4 4DT be said would discovering the fountain of youth. There United Kingdom is little experimental support and even less by way of evolutionary rationale in favor of a single "cause" of aging (Kirkwood and Kowald, 1997); anyone arguing that Podospora anserina aging must be a model for replicative senescence in human cells (or vice versa) is not Why Mutton Doesn't Taste Like Lamb helping either species. Clark's book is confusing, especially his definition of cellular senescence, which is un-Molecular Biology of Aging fortunate given that the importance of cellular senes-Edited by Vilhelm A. Bohr, Brian F. C. Clark, cence is the main thrust of his argument. It also contains and Tinna Stevnsner large chunks of basic cell biology that provide little rele-Copenhagen: Munksgaard (1999). 404 pp. vant background and would simultaneously stun a lay A Means to an End: The Biological Basis audience and bore an academic reader. of Aging and Death Successful books are usually written when a single By William R. Clark author sticks to what he knows best. One such example New York: Oxford University Press (1999). 234 pp. is Tom Kirkwood's Time of Our Lives, which covers the $27.50 evolutionary aspect of aging. The use of a single author makes for cohesion and interrelatedness between chap-Time of Our Lives ters. In contrast to Michael Rose's rather academic Evo-By Tom Kirkwood London: Weidenfeld and Nicholson (1999). 277 pp. lutionary Biology of Aging (1991), full of data and equa-$27.50 tions, Time of Our Lives is competing with Steven Austad's Why We Age (1997) for the wider audience. Writing a book on aging is as intimidating as trying to Both focus on two big questions for the lay audience: cover "the how and why of sickness." Asking "how we why we age, and what (if anything) we can do about it. age?" is almost as difficult as asking "how do we die?," The evolutionary perspective provides a much-needed insofar as it covers a vast array of tissues, physiological unifying thread in a field often marred by less than edifyprocesses, and underlying biological mechanisms. Three ing arguments between overenthusiastic supporters of recent publications provide contrasting examples of the various "causes" of aging, be they mitochondrial how to deal with this topic in book form. dysfunction, altered proteins, telomere-related cell se-Vilhelm Bohr et al. bring together nearly 30 papers nescence, or whatever. The tenor of these exchanges presented at the 1998 Alfred Benzon Symposium on is often that if a mechanism cannot explain all aging the Molecular Biology of Aging, covering such areas as everywhere then it must be irrelevant to any aging, anygenetic and population studies, replicative senescence, where. Understanding why aging has evolved provides biomarkers, and protein changes. This is a typical "cona powerful aid in understanding how aging mechanisms ference proceedings," with papers ranging from general might work, and many causes of aging proposed in the overviews to more specialized technical works. In espast are now recognized to be about as valid as the sence a bound collection of journal-style papers, a parmedieval idea that maggots originated from filth. Evoluticular attraction is that each section finishes with an tionary arguments impose a simple test for any "cause": edited transcript of a general discussion session conif there is no plausible evolutionary route whereby it ducted by the symposia participants. Despite nominally could have arisen, then it should be discounted. being a symposium on aging, several papers have wider The consensus among evolutionary biologists is that appeal, including several useful reviews on DNA repair. aging is not an actively selected process; aging was not Similarly, of seven papers devoted to replicative senesselected "for" any reason, such as altruistic benefits to cence, two are reviews on telomeres and telomerase the species as a whole, but rather it is a nonselected (predominantly in cancer) and telomerase-mediated im-"by-product" of selection for maximal reproductive sucmortalization. The book focuses more on molecular biology than on aging, but this does mean that it will interest cess in natural populations. This can be formalized in Book Reviews 695 the concept of antagonistic pleiotropy, which recog-altered phenotype might contribute to age-related tissue degenerations (Campisi, 1996). However, this phenome-nizes that in any age-structured population with progressively fewer individuals alive at older ages (even non did not evolve to cause aging, but rather as a barrier to tumorigenesis (Wynford-Thomas, 1999) . The accumu-if simply due to accidental death) the force of natural selection will dwindle with age. Thus, any mutation that lation of multiple genetic mutations during tumor development, with intervening periods of clonal expansion to confers improved reproductive success in the early years, even if associated with deleterious effects in later provide a sufficiently large number of target cells for the next mutation event, requires extensive cell division. life, will be selected for. Kirkwood's "disposable soma" theory (Kirkwood, Thus, any barrier to unlimited cell division will be a barrier to tumor formation. In evolutionary terms, this develop-1977) can be thought of as something of a "worked example" of this rather abstract population genetics mental program provides for reproductive success, since there is nothing more guaranteed to prevent repro-concept. Central to this theory is the concept of evolutionary trade-offs between somatic repair and reproduc-duction than being dead before sexual maturity. However, this requirement also brings with it the potential tion. The plight of the short-tailed field vole (described by one of my colleagues as "every predator's favorite for detrimental effects later in life. Although the intellectual rigor provided by evolution-junk food") illustrates this principle. In the wild, enthusiastic predation ensures that an enormously high per-ary considerations are a current strength in the aging field, they can only provide a framework within which centage of the members of this species soon end their lives with a crunch and a single terrified squeak. Those to ask questions about the validity of potential mechanisms and are powerless to suggest specific causes. that escape such "predation events" still face major problems with thermoregulation. Thus, the best evolu-The literature on causation is strong on observational data but weak on direct interventional tests. The pheno-tionary strategy for a vole is to channel the bulk of its resources (that is, energy from food) into reproduction type of the telomerase knockout mouse (Rudolph et al., 1999) has already provided the "proof of principle" that rather than somatic tissue maintenance. After all, there is no point in having a body that will last for a hundred experimentally imposing a reduced cell division capacity can produce a phenotype with many features of prema-years if your chances of seeing the year out are slim. When taken out of the wild and into the safer environ-ture aging. Similarly, the observation that replicative senescence in many human cell types can be prevented ment of captivity the consequences of this life-history strategy are what we call aging, a fact anyone who has by forced expression of telomerase (Bodnar et al., 1998) provides an obvious next test: in a species possessing ever had a pet rodent will appreciate. Bats provide a different example of a life-history strategy. Despite be-telomere-dependent senescence, does its removal (via forced expression of telomerase in animo) reduce or ing smaller than a pet rodent, some species can live for over thirty years in the wild. This shows us that there is remove any aspect of the aging of that animal in any tissue? Interventional tests similarly can be devised for no intrinsic biomechanical or developmental biological reason why a small furry animal cannot be designed to other mechanisms, such as asking whether increased aberrant protein production (such as via the use of misin-have a 30-year life span. Why voles and bats have evolved different life histories becomes clearer when corporating tRNA genes, making what might be termed a transgenic "error mouse") causes a premature aging one considers the protection from predation that flight confers (and probably the thermostable environment of phenotype. Until recently it was probably fair to say that the aging a cave). One challenge for the future is to understand the basis of this vole-bat difference in mechanistic terms. field lacked depth but had breadth to spare. Getting to grips with the primary literature is now impossibly time Problems in gerontological texts often start when authors begin to address which mechanisms cause aging, consuming, so a useful research tool for investigators who wish to understand human aging without having to probably because we really do not yet know the answer. Clark, for example, appears unwilling to acknowledge undergo it remains Ed Masoro's multiauthored Handbook of Physiology, Section 11: Aging (1995). Very aging mechanisms that might function at a level of complexity greater than individual cells in isolation, and he heavily referenced, at nearly 700 pages it provides an excellent guide to the primary biomedical literature re-largely ignores age-related changes in tissue structure such as those caused by "wear-and-tear." This is a valid garding human senescence. Similarly, Caleb Finch's Longevity, Senescence, and the Genome (Chicago, causal mechanism of aging for many organ systems for which there is no adult mechanism of replacement, such 1990) is an awe-inspiring magnum opus and remains the ultimate resource for anyone interested in aging as the teeth of herbivores or the ragged wings of aged Drosophila. Wear-and-tear fits well with evolutionary across the animal kingdom. Against these classic publications, how do the newer considerations, which argue that such repair systems would only evolve if there is selective pressure to do works compare? Clark's A Means to an End in particular does not fare well. Although a valiant attempt to cover so. As proof, there are numerous special cases where this has indeed occurred, such as continuous tooth re-such a massive field, there are no major new insights or perspectives into the aging process, and most of placement in many species of shark. Another example illustrates the power of evolutionary the topics are covered with greater detail and quality elsewhere. Kirkwood's Time of Our Lives, as would be thought when applied to a potential mechanism of aging. The limited division capacity of human cells in culture expected from a leader in the evolutionary field, is excellent on this topic. There are moments of unintentional (replicative senescence), when coupled with analogous in vivo cell division during life, has been argued to lead to humor, such as the anecdotal vision of a nude Tom Kirkwood prostrate in the bath where "it suddenly the progressive accumulation of senescent cells whose Cell 696 dawned on me why aging occurs" (p. 63), a scene from vertebrates based on adult and embryonic morphological data, respectively. Their disagreement regarding the history of ideas over which a blind (or even a small whether comparison of adult structures or comparison flannel) could have been decently drawn. The book only of developmental sequences would allow the accurate really falters when it strays away from evolutionary matreconstruction of phylogenies was taken up by their ters, with the bathwater clearly cold by the time his respective students in one of the most raucous and thoughts turn to cancer biology and cell senescence. vicious debates in the history of biology. By the time However, of the various books aimed at the wider audithe debate ended, most biologists were skeptical that ence, Austad's Why We Age (1997) is the one I would either type of data would allow the reconstruction of personally choose to give to a lay person or a graduate phylogenies. student new to the field. Despite an unfortunate hagio-Now, after almost a century, research programs in graphic tendency, it is full of wonderful anecdotes and developmental and evolutionary biology are undergoing examples, and superbly conveys the intellectual excitea rapprochement spurred by the development of new ment that fires many to work in this area. methods of comparison (cladistic phylogenetics) and insights into the molecular basis of development. Not David Kipling surprisingly, larvae are again playing an important role, Department of Pathology as biologists explore Walter Garstang's axiom (Zoo. J. University of Wales College of Medicine Linn. Soc. London 35, 81-101, 1922) that ontogeny does Heath Park not recapitulate phylogeny but creates it. In spite of the Cardiff CF14 4XN important roles that larvae have played in the origin and United Kingdom subsequent evolution of metazoans, it is amazing that biologists still can not agree on a definition of what References larvae are, when they arose, how they evolve, and the nature of their role(s) in complex life histories.
doi:10.1016/s0092-8674(00)81493-2 fatcat:xrb75l6plngndjwh3kwuewikb4