Despite the economy has been recovering since the 2008 crisis, many biology labs are still facing funding issues. Part of the funding issues has resulted from funding changes in the overall federal budget destined to science. A funding decrease or stagnation for science does not only affect the number of science projects, but also a training system that was designed at a time of expansion, which is training an excessive number of PhD’s, post-docs that can not find enough employment positions. But the funding decline does not seem to be occurring equally in all fields and approaches to biology. Some of the new key initiatives, such as the eight new Systems Biology Centers initially funded by the NIH, which were later expanded to 10, have stopped being funded. These include the Chicago Center for Systems Biology, which had many projects that mostly used model organisms to learn basic regulatory principles at the systems level. Not only new institutes devoted to emerging fields such as systems biology are being compromised, but approaches to science that have a well established track record of providing key discoveries. A paramount example is the funding decline in the number of NIH funded grants using model organisms such as Drosophila. In this blog entry I will use the study case of fly research to illustrate the extent by which model organisms have contributed to key insights in many areas of modern biology and medicine. I would then comment on possible consequences and reasons the funding agencies might have to downsizing such important approach.
Successes of the fly – a paramount example of the model organism paradigm:
Since the beginning of the 20th century flies have been a used as a model system to study basic principles explaining how biological systems function. Due to space constraints, I will only mention a few of the many key contributions that flies have made in the past century. I refer the reader to a recent review on the subject that presents a more detailed account with all the relevant references (1). During the first halve of the century Drosophila was a center player in the formation of a modern, chromosome-based theory of heredity. Thomas H. Morgan and colleagues made the first genetic maps for any organism, also discovering the sex linked hereditary phenomena, which have been central to the understanding of sex specific differences in development and expression. The genetic map developed by Morgan and others showed that genes could be arranged linearly on a chromosome and that spatial relationships could be deduced from calculated recombination distances. Morgan was awarded a Nobel Prize for his contributions, which not only resulted in the establishment of genetics as a central piece of modern biology, but also allowed a the subsequent development of new evolutionary models, based on genetic arguments. Decades later, with the advent of molecular biology, once a marriage between genetics and developmental biology occurred giving rise to “developmental genetics”, flies were used to discover key regulatory factors affecting early embryonic patterning factors, a discovery that was also awarded with a Nobel Prize to E. Wieschaus and colleagues. But the contributions to patterning did not only remain in the early factors, but also on later acting ones, key to pattern the parts of the body such as the hox genes, which are highly conserved in flies and humans. Later, flies were used to discover the basic principles of immunity, another discovery for which a Nobel prize was awarded. More recently, flies have also played significant contributions to new blooming fields such as all the newly discovered RNA-based regulatory phenomena, such as siRNAs, microRNAs, piRNAs, etc.
But flies have not only contributed to the discovery of fundamental principles of biology. The relevance of the contributions made using flies as study subjects resides in that such discoveries have greatly illuminated human biology, both in the normal and pathological case. Components of the Epidermal Growth Factor Receptor (EGFR) network, including the human homologs of EGFR, Ras, and the “down stream” transcription factors, were originally discovered in the fly studying phenomena such as embryonic and eye development. Despite such phenomena might have initially been perceived by some as unrelated to human biology and disease, cancer studies showed that it were these key factors that allow cells to talk to each other in the context of a tissue and organ. It was precisely key signaling pathways such as Notch and EGFR signaling, which have been very frequently found to be disrupted in human cancers. Overall the fly and the its development, specifically the patterning of its organs, have made key contributions to the understanding of human disease.
NIH Funding Decline for Model organisms in US.
A recent review written by Wangler, Yamamoto, and Bellen (2015: I refer the reader to the graphs present in this review) has shown two what extent NIH funding has very significantly decreased for fly research. This funding decline has continued over the years, and is not just a result of the 2008 economic crisis. If the current reduction trend continues over the next decades fly research will be significantly reduced, and the fly golden era would be a thing of the past, mostly of interest of historians of biology. NIH seems to be shifting towards cell-line based biomedical research. I suspect that such shift results from a view in which it is thought that human cell lines are after all closer to humans than flies, worms or yeast, at least when it comes to deciphering key human biology principles. It is true that at least such systems share a more similar genome, and perhaps potentially closer regulatory mechanisms, but they might not necessarily always make possible deciphering all the underlying biological principles. Ultimately, reducing funding for model organisms arguing that human cell line-based research is better that the use of model organisms downplays the role of the organism, and evolution in how discoveries are made. I will expand these two claims in the next paragraphs.
Downplaying the evolution and the organism:
Recently, during the first plenary session talk of the 2015 Drosophila Research Conference, Dr Allan Spradling showed the parallels of what initially were considered dissimilar (non-homologous) phenomena such as oocyte production in flies and humans. He not only highlighted and how fly research contributed to the understanding of the human case, but conclusively showed how the model organism paradigm is conceptually based on Darwinian principles: common ancestry implies homology and thus deep conservation of mechanism. Off course such conservation depends on evolutionary distance, and not every phenomenon is conserved to the same extent. But conservation of networks and regulatory principles are so deeply rooted in our common evolutionary history, that what might have appeared to the general public and even to expert scientists as dissimilar and in principle “unrelated phenomena” between flies and humans, research has shown that actually hold common regulatory and architectural principles and thus underlying general mechanisms. We share a common toolbox of molecules and interactions, that evolution has expanded and repurposed to accommodate additional complexity. Thus, preferring human cell lines over model organisms to deepen our understanding of human biology ultimately implies downplaying the potential contribution of discovery based on evolutionary conservation.
The new apparent NIH tendency of preferring human cell-based research over model organisms is also pragmatic: it tends to emphasize the cell over the organism. Under such a view tissue, the organ, and the organism levels of organization, and the regulatory principles that operate in trans at those levels, play less of a significant role in the establishment of and cure of disease, and are less relevant for understanding biology, not just human biology, as a whole. Most eukaryotic cell functions evolved in the context of multicellular organisms in which they have been embedded for millions of years, and thus it is not only plausible but absolutely certain that their function under normal and pathological cases would have to be studied in the context of the constraints of the organism, even in the case of cancer, in which cells seem to try to defy such organismal constraints. Cell-line base research is necessary and very useful to make screens, to test candidate drugs, do biochemistry and even measure single cell dynamic phenomena in vivo in cases in which a whole model organism make it difficult to get acess to the cell of interest. But recognizing the tissue, the organ and the organism as key subjects of study, seems also important because many of the regulatory layers respond to fluctuating signals that come from trans phenomena, that is, cells in other parts of the organ or even from different organs, or compensatory mechanisms that require the whole organism to be maintained and studied.
Last, researchers frequently complain that cell-line based research very frequently lacks reproducibility. There is a concern about such lack of reproducibility, and even companies complain that they can’t reproduce results established using cell lines. Part of this is because cell lines are frequently not stable over time: researchers usually thaw frozen aliquots of them, pass them a few times and need to be discard them, because experiments done on them do not always provide reproducible results after they have been maintained in culture for many generations. In contrast, the fly community (I my self have used them) has available mutants that were isolated by T. Morgan himself, almost a century ago. Such a remarkable difference over the stability of phenotype suggest that the tissue, organ and organism, and the sexual reproduction events that every generation goes through, must act as key players to even maintain the hereditary basis of the material used for study.
Overall, reducing the organism to its cultured cells, and downplaying the use of evolutionary conservation to guide the study of normal and pathological behaviors of cells seems a possible but limiting strategy. During the 2015 fly conference Dr. Angela dePace suggested that the fly embryo, and particularly the stripe two of the even skipped expression pattern “is the operon lactose of developmental biology”. Such a phrase implies that developmental phenomena in the context of multicellular organisms is not only the work horse that should be used to understand how DNA sequences and transcription factor binding to sites in enhancers regulate expression patterning in multicellular developing organisms, but it also implies that such phenomenology is irreducible and needs its own minimal complex study system that is above the cell. Patterning and abnormal development goes beyond cell lines and individual cells as components, since it requires phenomena like morphogen gradients, or even compensatory physiology that occurs during normal development, which involves regulatory networks operate in trans across the organism tissues and organs. Reducing funding for model organisms might not only hinder pace of discovery of new phenomena such as RNAi, miRNAs, piPNAs, originally done in model organisms sich as worms,but it implies that we will even miss the chance of fining cures in which affected organs or diseases are treated in trans using whole organism regulatory loops. lSuch loops that might not even be easily discovered using cell line based strategies. Also, reducing funding to model organism labs might disproportionally affect either younger non-established investigators or more risky proposals using model organisms, since it is less likely that labs of established PI’s with less risky approaches that have had R01 grants for the past decade will see their funding reduced in number of grants over the coming years. For the reasons stated above I am a strong proponent of maintaining the model organism paradigm as a key research approach to gain new biological insight about human biology.
References:
(1) Michael F. Wangler, Shinya Yamamoto, and Hugo J. Bellen (2015) Fruit Flies in Biomedical Research. Genetics, March 2015 199:639-653.
Image credits:
The fruit fly Drosophila melanogaster, a favorite model organism of many biologists. Image taken from: http://en.wikipedia.org/wiki/Drosophila_melanogaster