Friday, September 23, 2011
Monday, April 19, 2010
Reading Carl Zimmer’s Microcosm: E. coli and the New Science of Life, I came across a reference about aging in E. coli – a 2005 PLoS Biology paper “Aging and Death in an Organism That Reproduces by Morphologically Symmetric Division.” Four researchers from France described their measurements of individual E. coli cells growing old.
I know all this sounds like a fairy-tale. After all, we tend to see the life of bacteria as immortal. Making up a kingdom of life that populates every corner of the earth, they seem either to keep dividing actively or to wait for such chances in their dormant forms. Once upon a time, our awe for their vigor was even expressed in our hypothesis that they enjoyed a fictitious everyday spontaneous origin. The news, that bacteria generate wrinkles and diseases for themselves, dropping into the 21st century ears, perhaps sounds even stranger than that that fiction in the 19th century.
Having played with E. coli for five years, I have indeed seen their deteriorations for a few times. Once E. coli liquid cultures are set up, the inoculated cells, often invisible initially, would start to glut the rich nutrients, and multiply into dense crowds overnight, which give the cultures cloudy appearances. Left in the incubator for more than two days by, for example, inadvertent researchers, however, they would deplete nutrients and shrink into dilapidated films. This is no surprise since all life forms require some source of energy. But this is also not what the authors mean by aging E. coli. They do not mean degeneration or death caused by famine or other harsh environments. They were serious in a deteriorating process that was dependent solely on the growth history of cells in a wholesome environment.
Growth for E. coli means cell division. Rod shaped, they would produce progeny through elongation, and sever from the middle of the cell bodies into two rods. In each division, Eric Stewart et al. define the end of the E. coli progenies that utilized their mother’s end as the old pole; the end generated anew as the new pole (see the figure below). The authors monitored the process of cell divisions from one cell to up to 500 cells (see the video), and ask the question: do the cells incorporating older poles behave differently from cells with newer poles?
The authors measured specifically of how fast the newly generated cells from divisions started the next round of proliferation. They observed that, indeed, within the same generations, the cells with older poles took longer to start dividing for the next time. Across generations, the difference in reproductive rates also widened: the more generations the old pole went through in a cell, the longer it took to initiate the next round of division. In the end, 16 among about 500 cells could not even start dividing any more, therefore were defined “potentially dead cells.” The authors deemed such phenomenon reflecting an aging process that involves declined rates of reproduction and increased death rates in bacteria.
There had been much publication before 2005 showing that some fungi or bacteria can divide asymmetrically, thus dumping most of their old biochemical trash to one of their progenies, making them senescent, while keeping the other offspring rejuvenated. The significance of the research by Stewart et al. lies in that they showed even morphologically symmetrical divisions can produce aging of there progenies, because a chemical or structural symmetry can never be absolutely achieved in cell divisions. The authors further hypothesized that this bacterial way of aging may provide a relic that still contribute to the aging of more advanced organisms.
With neat design of experiments and interesting discussions, however, this research triggered my qualms. In most basic consideration, I doubt whether the correlation between “old poles” and declined rates of proliferation indicate a biologically real state of aging. It might have been a growth signaling mechanism, like quorum sensing (bacteria release chemical to reduce the reproductive rates when the population reach higher density), to which old poles hypothetically have more reactivity.
Another doubt concerns with the fate of the species of E. coli. According to the authors, the reproductive efficiency would keep diminishing as E. coli cells proliferate. As the old pole becomes ever older with each division, the cells would eventually stop dividing at all. Unlike multicellular organisms, which enjoy the magic of rejuvenation in their germ cells, E. coli without a generational rejuvenation seems to be doomed. Indeed, while more advanced organisms age as individuals, the symmetrical aging of microbes is synonymous to the aging of their species. If E. coli has its own elixirs, or a hypothetical one, it should not have escaped from the scope of the authors’s discussion.
The third group of considerations is more philosophical: to what extent can we really define the loss of reproductive power as a sign of aging, especially for individual cells? If the “age” situation in dividing cells are determined more by the structural and chemical conditions of a cell, not by the passing of time, why should we call such conditions “aging” processes? If such aging of microbes contribute somehow to our aging evolutionally, can we also say it in a reverse way, that this misnomer of aging in E. coli is only a relic from our lasting consideration of the aging in our species?
Yes, no one is immortal. But is saying that equal to say that every living thing is aging?
Wednesday, September 23, 2009
There exist a variety of ways for scientists to go about studying aging. Ever since the creation of the biology of aging as a field with the hope of addressing emergent problems associated with global population aging, this complex subject has triggered myriad scientific imaginations. Some hold that aging is a developmental stage, which manifests itself through breakdowns of various physiological architectures, thus understanding aging relies on studies in developmental biology. Others disagree, emphasizing the role of environmental damages and errors in protective machinery of organisms. For example, one research program studies the age-related dynamics between the processes of the damage and repair of DNA, molecules that carry the information of life. Yet others do not regard the mechanism of aging, whatever it is, is as important as the physiological programs that ensure individual life span. Centenarian genetics, and the molecular signaling triggered by caloric restriction, fall into the category of studying biological basis of life span and longevity, whose results often feed the drug development industry with potential schemes of making “Elixir”.
In some sense, even the most brilliant mind in biology can only grasp limited aspects of aging. When a group of curious blinds poke around a big elephant, however sensitive and discerning they are, what they learn largely depends on the particular location of their footholds. In the case of biogerontologists, the scientific footings are constrained by various theoretical predilections and experimental arrangements. But still, where does those diverse footholds come from?
The author visited the Intramural Research Program of National Institute on Aging (NIA) located in Baltimore for an afternoon this August, chatting with six researchers there. Those conversations were initially intended to help explore the landscape of aging research, and they turned out to shed light on the lineage of various takes of aging among biogerontologists. As a nascent branch of biology and biomedicine, the study of aging does not enjoy many researchers trained native in the field. Most of them came to focus on aging from the trajectory of their original studies, along with their former disciplinary leanings. Consequently, the approaches in aging are often the fruits of cross-fertilizations between the motive of studying aging and the methods from branches of biology and biomedicine.
David Schlessinger arranged the marriage between genomics and the study of age-related disease. Having worked for his PhD in Harvard in the wake of the discovery of the DNA “double helix” in the 1950s and thereafter a researcher in the Pasteur Institute on gene regulatory expression in bacteria, Schlessinger joked that he always ended up in the right place at the right time. His timely contribution also includes a 10-year direstorship of the Human Genome Center at Washington University. Witnessing the unfolding of human genome, Shlessinger regarded the technologies needed for genetic and genomic study on human aging became mature. Geneticists could now identify the different genetic sequences and expression patterns between phenotypically differed cohorts using chips and locate relevant loci on chromosomes through database at researchers’ fingertips. In 1997, he undertook the position of Chief of the Laboratory of Genetics in NIA. Working along the methods of genomics and population genetics, he constructed X chromosome map, discovering a number of disease genes, some of which related to human aging.
Sige Zou focuses his research on the change of life span in fruit flies and round worms brought by dietary restriction (DR) and deprivation. The research on dietary restriction is booming in the field of biology of aging, although many deemed the prolongation of life made by DR is not much more than a laboratory artifact. It combined the knowledge gained through decades of study in model organisms such as D. melanogaster and C. elegans, with molecular biology of nutrition signaling, and translational efforts. In such programs, not aging, but the mechanisms of life span and those of longer life span, are under investigation.
The researchers the author talked to also include Weidong Wang, who brought his experitise in biochemistry to the study of a progeric disease, Fanconi anemia, and Yie Liu, who transferred her molecular study in cancer cells, with considerations on DNA repair and telomere maintenance, into the study of cells at the intersection of senescence and malignancy.
Developed late relative to other subdisciplines of biology, the biology of aging became a topic that engaged a variety of existing methods from other branches and adapted them into its own utilization. The lack of consensus on the causes of aging, and the prioritization of research on various age-related diseases further expanded the purview of biology of aging, allowing researchers from many fields wield their disciplinary skills. The discrete but multiple scientific programs welcome alternatives in researching aging, which made complementary studies possible. However, also due to this status quo, the limited resources of aging research are dispersed into scattered efforts, which may inhibit the productivity and efficiency of the truly important approaches. In addition, how to connect the dots derived from various approaches into a coherent understanding of aging is an issue yet to resolve. A tentative question is whether it is possible to combine various approaches and melt them down to a grand methodology of aging research in biology, without compromising the current richness and diversity. Before those questions are answered, the biology of aging will continue to display its exceptional chirography in theoretical diversity and experimental multiplicity on its scientific frontier.
For CSPO soapbox.
Wednesday, July 22, 2009
The idea that cancer and aging may be related or even share some common features was not a conclusion intuitively reached by armchair thinkings. Although there is a clear correlation between age and the frequency of onset of cancer, on the cellular level, it is quite hard to imagine what cancer, characterized by incessant cell proliferation, could have anything to do with aging, which suggests a transformation of cells into more lethargic state in most circumstances. However, from the 1960s until now, the parallel study of both phenomena and the communication between them led scientists to the recognition that cancer and aging share many biological grounds.
Finkel et al. 2007 gave pretty thorough a review of the common biology between cancer and aging. They even took pain to mention several historical aspects, pointing to the once nebulous clues found in laboratories that suggested the link between cancer and aging. Indeed, the clues came from many fields. Cell culturists Leonard Hayflick found the upper limit of cell division when he was in the middle of his subculturing routines and suggested there must be a shared mechanisms to determine the fate of the cells, either aging or proliferative malignancy. p53, an initiator of cellular senescence, was initially discovered first as a repressor of oncogenesis. Telomere, the once alleged determinator of life span, was proved to be vital to most of the cancer cells as well. As the author said for several times, this may mean that a treatment for cancer may involve accelerating aging processes. However, cancer and aging are not clear-cut opposites sitting at the two ends in the cellular fate. They displayed similar behaviors as well. They both lack sufficient maintenance for genome stability, and they do not keep enough activity of autophagy for waste management. This shared shortage of cancer and senescent cells may suggest a common ground to slow down cancer and aging by one intervention.
Those authors thanked Henrietta for her inadvertent contribution of her cervical cancer cells, denoted later as HeLa cells. They probably could have added the importance of many fetal cells raised in cell cultures as well. Although those cells could not compete with HeLa cells’ longevity in the dish, they nevertheless provided the sheer contrast in cellular behavior between normal cells and cancer cells, illuminating the first hint about the existence of an underlying mechanism that determines cellular mortality (aging) or the escape from it (cancer).
Finkel, T., M. Serrano, and M. A. Blasco. "The Common Biology of Cancer and Ageing." Nature 448, no. 7155 (2007): 767-74.
Sunday, April 19, 2009
Hayflick and Moorhead, 1961)
In the late 1980s, four scientists reached similar conclusion towards an enigma in cell biology: the mortality of normal cells. Or, if you wish to frame the question from the other direction, why some cells, like malignant tumor cells, can reach immortality. The ways those three scientists approached the question, however, were quite dissimilar. One of them applied a procedure much like detail cataloging, another crossed cells holistically, another two took advantage of a viral probe to dissect the cellular machinery.
The conundrum sprang out of an influential discovery by Leonard Hayflick. Opposing to common belief, Hayflick serendipitously found human normal cells can not divide infinitely in cell cultures in 1961. The logical question followed was what mechanisms control the timing of the cessation of cell division. Parallel to typical theoretical debates in aging research, there was dichotomy in explanations about cellular senescence in terms of damage or genetic control.
More than two decades passed before the researchers advocating genetic control in cellular senescence constructed some experimental anchorages. They actually called this genetic control a “terminal differentiation”. They held, as how hematopoietic stem cells generate erythrocytes, the senescence of cells in culture was due to a process programmed by expression of differentiation factors.
Vincent Cristofalo apprehended the question of cellular senescence initially by cataloging the biochemical difference between dividing cells and senescent ones using meticulous molecular detection and measurement. As early as the mid-seventies, he listed dozens of biochemical changes as cells senesce. One feature Cristofalo characterized was the low activity in senescent cells of thymidine triphosphate (TTP) synthesis, a process which prepares DNA building blocks. In 1980s, Cristofalo realized the significance of this detail among many others. Since TTP synthesis only happened in late G1 phase in mitosis, Cristofalo proposed that the senescent cells are actually arrested in the late G1 phase. The cell cycle research was flourishing during 1980s and Cristofalo suddenly found himself in a large pool of literature about factors determining such arrest. Thus to obtain larger samples of ores might be advantageous, but to sharply discern real gold is definitely more important.
James Smith viewed cells as hodgepodges of various factors, in which some factors should be dominant and control others. Smith was inspired by revealing cell hybridization technique in genetic study and applied it to the fusion of senescent cells and proliferating ones. The resulting heterokaryons demonstrated senescent features and Smith proposed that the senescent factors were dominant and they should be inhibitors of cell divisions at large. This cell hybridization experiment started his pursuit of characterizing those inhibiting factors by more cell hybridizations, as well as extraction and microinjection. Much like how one can judge persons, one can characterize features of cells by evaluating how they interact with other cells as well.
Jerry Shay and Woodring Wright wielded audaciously a probing tool, Simian Virus 40 and its functional protein, large T antigen, to those senescent cells. They showed that large T antigen would make cells dividing longer before they reach yet another end with quite different characteristics to the former senescence. Thus the cells with large T antigen would bypass one boundary of mortality but not the latter hapless fate. Since it was already known that large T antigen binds many molecular targets, one or multiple of targets might be the factors in charge of the first mortality. While the large T antigen meddles with the mortality 1, the final declining fate of cells manifests another senescent phase, the mortality 2.
As the science of cellular senescence unfolded, mortality 1 were assigned many coordinating factors, including p53 and RB proteins, while mortality 2 were deemed to be most relevant to telomere and chromosomal stability. Since the subsequent development was regarded to be relevant to biomedical application, it gained much attention. For telomere and telomerase, much hype. The epistemological exercise was unnoticed as always, although it has much to tell about how the telomere story was constructed and can be evaluated. From the convergence of notions between the scientists who perhaps can be comically categorized as a phenomenologist, a cell crossbreeder, and two molecular interveners, the implication is twofold. On one hand, scientists captured traces radiating from one phenomenon in distinct ways, which might be hard to assign to certain paradigm, if not “research traditions” or “research programs”, but would be interesting to evaluate in terms of the epistemological level of outcomes each approach can generate. On the other hand, it shows how ridiculous it is to degrade a multi-cause, multi-step process into a linear change of one molecule, without contextualization in science or in history.
Thursday, December 18, 2008
It all started with an answer I gave, in a typical pragmatic style of scientific proposals, to Professor K’s question what my paper would contribute to history of Tang or history of science. “The paper should be a critique of industrialized life, to inform the western world with an alternative living style,” I said. The answer obviously did not satisfy, but seemingly astonished him. Since then, I was looking for what really defines a history work, other than how to make a use of it, like what social scientists, economists etc. do.
Professor J recommended me to read The Landscape of History written by John Lewis Gaddis. Gaddis is a famous Cold War historian. He wrote The Landscape during the year spent in Oxford with no specific obligations. This precious year was made possible by a big fellowship called George Eastman Visiting Professorship that has accommodated other celebrity scholars like Linus Pauling and Felix Frankfurter. A professor set free indeed, Gaddis set out to discuss what history is about and how historians do it. The Landscape is dedicated for historian cubs and more generally for his fellow historians, because not all of them can articulate what history is about, or think this articulation is of any importance.
Gaddis provides a timely lesson. For my case, surrounded by scientists and social scientists, I did suspect if history has any methodological rigor. Anyway, telling a story based on manuscripts and correspondences can not really be regarded scientific, but I guessed trying to judge history as scientific or not is off the point – history has its own value as a record system and an art. Nevertheless, the “science envy” became a promoter to increase methodological rigor in humanities for the last several decades. That is why social sciences have been obsessed with “teasing out” independent variables from the dependent ones, while Gaddis himself just could not imagine the possibility that any social factor in reality exists in an “independent” mode. In defending history, Gaddis used a quirky way in defining science first. He says, look, while the social scientists are drudgingly emulating natural science by their awkward models which are far from reality, several branches of natural science have found the importance of narratives and become more history like, such as cosmology, ecology and paleontology. What defines science, consequently, is not its experimental methodology but its fitting representation about reality. With this methodological “passing of ships in the night”, historians should be proud because, first, they do not inflict themselves with erroneous assumptions about the existence of “independent variables” or concern themselves with the impossible task of making history a precise science; second, by doing so, they have already resembled some of the most interesting branches of natural science.
Comparing those history-like sciences with history, Gaddis brings a lot of analogies between history methods and those from other fields into his book. There is always danger of overusing analogies, and he is quite aware of it. He absolves himself from the guilty of overuse, or sometimes, misuse of analogies by saying that anyway, these comparisons serve only as metaphors. Thus when he compares historical scales to the structure of fractals, or when he tells a parable about historians’ work by describing how paleontologists design a representative skin according to the remaining skeleton of a dinosaur, we would forgive his impreciseness, or even learn to appreciate his pedagogical elegancy to make abstractions empirical. After all, Gaddis’ initial aim is to name the unnamed or the assumedly unnamable in the discipline of history. In light of the difficulty of the task, metaphors are invaluable helps to import the link from the familiar to the unfamiliar.
Caspar D. Friedrich’s art The Wanderer above the Sea of Fog serves as the main metaphor for history study and also the cover of the book. A man standing on the rocks, facing the fog covered terra, contemplates on what are happening before him. By gazing the vast terra from high, he would probably feel both empowered and diminished. I felt a sense of mission staring at this man’s back, assuming he is indeed a historian. After all, not all people climb to the rock, the vantage point, where historians stand, and try to grasp the past.
Final thanks to Gaddis for providing what I was looking for.
Sunday, December 7, 2008
As implied before, Brady not only attempts to depict this scientific heroine’s life, but also to shed lights on discourses on sociology, philosophy of science with her biographical approach. In a moderate sense, her work used “collage, narrative discontinuity, multigenre narratives, unsuspected time-shifts”, as Söderqvist suggested, in order to illuminate the links between a significant individual’s life events and scientific development in larger scale. An invaluable experimental attempt as it is, however, Elizabeth Blackburn probably will not fully satisfy either public readers or historians of science, due to its ambivalence between a person and a career as the subject matter. The most-likely readers may remain in the scientific community itself, if the latter would pardon Brady’s public oriented treatment of technical terms. Especially, to read and contemplate on the messages about scientific excellence Brady brings out can be more than helpful to a novice of molecular biology and biochemistry.