Wednesday, September 23, 2009

One afternoon in NIA: on the variegated landscape in biology of aging

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

Cancer and Aging: the Yin and Yang of Cells?

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

Mortality 1 and 2: the Divergence of Cells and the Convergence of Science

(In the picture, left: proliferating cells, right: senescent cells.
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.