- Email: [email protected]
The Unaimed Arrow Never Misses
CHAPTER THIRTY-ONE
The Unaimed Arrow Never Misses Raphael Kopan1 William K. Schubert Professor of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA 1 Corresponding author: e-mail address: [email protected]
Abstract In this assay, Raphael Kopan argues that focused emphasis on disease and translation stifles innovation, and outline the reasons why, in my opinion, developmental biologists are more likely to produce new and important discoveries than their more "focused" colleagues.
We are celebrating the 50th anniversary of Current Topics in Developmental Biology, started by Drs. Aaron A. Moscona and Alberto Monroy. I had the unique privilege to have been mentored by the late Aaron Moscona, bringing with it the opportunity to spend valuable time with him and his wife Malka, both of whom were exceptional developmental biologists, teachers, and colleagues. They are responsible for transforming my budding fascination in Developmental Biology into a life-long pursuit. It is highly appropriate therefore to contribute this essay in part to commemorate one of the founding editors of this series. In the last 50 years, we have seen our field ascend to a peak with the elucidation of the mechanisms underlying the major signaling pathways, a fundamental understanding of the genetic pathways regulating pattern formation, which was recognized by the 1995 Nobel Prize in Physiology or Medicine to Edward (Ed) Lewis, Christian ( Janni) Nusslein-Volhrd, and Eric Wieschaus, and the seminal work of John Gurdon, who laid the foundation to one of the most transformative discoveries of the twenty-first century, induced pluripotency (shared 2012 Nobel Prize in Physiology or Medicine with Dr. Shinya Yamanaka). Sadly, by that time, many Current Topics in Developmental Biology, Volume 116 ISSN 0070-2153 http://dx.doi.org/10.1016/bs.ctdb.2015.10.007
#
2016 Elsevier Inc. All rights reserved.
547
548
Raphael Kopan
developmental biologists interested in stem cells defected to create their own specialized discipline, publications, and meetings. This latest blow together with the overall decline in funding driven by the blunted, short-sighted vision of Congress and thus, the NIH, are the most important factors in the present state of our beloved discipline driving students and postdocs away. But, why should we care? Isn’t the “wisdom” of group science and disease focus self-evident? Developmental biologists are generalists. To paraphrase Sydney Brenner, I see developmental biologists as retaining a working multidimensional zoom, allowing them to travel in scale and in time and through any appropriate model organism, to continually convert original observations into discoveries of unexpected new mechanisms with relevance ranging from basic biological mechanisms to human disease. In this analogy, cell biologists rarely zoom up to the organ and the organism levels, while the stem-cell biologist are not always interested to zoom forward in time to look at the differentiated cells or organ. A stem cell biologist may look at stem cell aging only as an obstacle limiting the function of a perfect regenerative engine. In contrast, a developmental biologist would consider stem cell aging as a component in a complex developmental program that matches lifespan with the mode of reproduction (sexual vs. asexual), reproductive strategy (K vs. R), and niche availability. Only developmental biologists with a working zoom lens and a self-issued license to ponder any and all of these subjects, would consider all of them fair game. Perhaps I convinced you that this analogy has some merit, or perhaps not. Yet you wonder—so what? What is the advantage of a working multidimensional zoom? This seems so unfocused, slow, and counterproductive. We live in an era with heroes driven by focused, fast paced progress. Fixing on stem cells or neurons or T-cells only accelerates our ability to translate, utilize, commoditize, and monetize. True, but focus comes at a price. It reduces our ability to innovate. Innovation occurs in our peripheral vision, and only if we are willing (or feel entitled to do so because we are developmental biologists) to avert our gaze from the target and explore that observational flicker. Sure enough, it slows progress towards the target. But, it increases our chance to experience serendipity. Horace Walpole coined this term in 1754 to describe those “always making discoveries, by accidents and sagacity, of things which they were not in quest of.” Things you are not in quest of? So unfocused. Serendipity gets us involved in areas where we lack expertise, amplifying its benefits. Again paraphrasing Sydney Brenner, this allows one to
The Unaimed Arrow Never Misses
549
re-embrace one’s ignorance, to use it as a sharp scalpel, to think outside the box and ask “stupid” questions. Ignorance was instrumental in my own work on Notch signaling. I simply did not know anything about how signals were supposed to be propagated, and I worked with a mentor (the late Harold Weintraub) that felt no need to educate me on that point, allowing instead for the experimental path I took to unfold as it may. I learned first hand that when we apply a rigorous scientific method, and keep an open mind, we can make important discoveries we were not in the quest of: my target in those early days was to find genes involved in hair follicle development (Kopan & Weintraub, 1993). Residual Notch expression in the presomitic mesoderm (unrelated to hair biology) lead to an assay, which lead to the observation that active Notch constructs that could repress myogenesis had to reside in the nucleus, that lead to the hypothesis that Notch somehow had to get there in order to function, and so on. Of the many examples I can choose, lets consider how RNAi was discovered. The use of antisense DNA or RNA was commonplace at the time Kenneth Kemphues was investigating the PAR genes. However, Su Guo and Kemphues were the first to note the absence of strand specificity and the effectiveness of dsRNA in gene silencing (Guo & Kemphues, 1995). That was not what they were in the quest of, but they reported it anyway. The significance of this sidebar was not lost on a pair of developmental biologists, Drs. Craig Mello and Andrew Fire, already distracted from their respective quests by peripheral observations. As Dr. Mello recalled1: “The power of this gene-silencing approach accelerated our studies and we began to make rapid progress in understanding the developmental mechanisms that specify cell fate in the early embryo. However, we also became interested in the silencing phenomenon itself. The first observation that truly galvanized my interest occurred when, having injected RNA targeting apx-1, a gene essential for embryogenesis, I observed by chance that some embryos hatched and matured to adulthood only to produce 100% apx-1 dead embryos. The silencing phenomenon had skipped a generation and had been passed on via the germline to the next generation! This was truly amazing and prompted further studies that demonstrated the transmission of silencing for multiple generations via both the sperm and the egg… discovered, in part by accident while [a graduate student was] learning to inject…These findings, along with the inheritance properties, and the lack of strand specificity (first noted by Guo and Kemphues), prompted us to 1
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/mello-bio.html.
550
Raphael Kopan
recognize the silencing phenomenon as an active response in the organism to the RNA.” This paragraph twice highlights the gravitational pull of a peripheral event, which combined with a prepared mind propelled these un-focused colleagues to a transformative discovery recognized by the award of the Nobel prize in Medicine, 2006, to Drs. Mello and Fire. The odds that a scientist with complete focus on human health would have discovered RNAi are minuscule. The larger the umbrella, the greater the opportunity we may engage in exploring things we were not in the quest of. I have gotten to the age when students decades younger than me lament that in my student years, discoveries were easier to come by (I confess to having the same concern learning about the birth of molecular biology (Weiner, 1999)). Now, they say, all the “good stuff” has been discovered. To that I reply: nonsense! We have only scratched the surface of what is yet to be discovered. Your problem is that you are too narrowly focused. Become a developmental biologist; claim all of life as your domain, and follow your peripheral vision.
ACKNOWLEDGMENTS The author wishes to thank Drs. Brian Gebelein, Kenny Campbell, Aaron Zorn, and Jeff Whitest for commenting on the chapter, and Tal Kopan, for expert advice and encouragement. R.K is supported by NIH RO1 GM55479.
REFERENCES Guo, S., & Kemphues, K. J. (1995). par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 81, 611–620. Kopan, R., & Weintraub, H. (1993). Mouse notch: Expression in hair follicles correlates with cell fate determination. Journal of Cell Biology, 121, 631–641. Weiner, J. (1999). Time, love, memory: A great biologist and his quest for the origins of behavior. New York: Knopf.
The Unaimed Arrow Never Misses Raphael Kopan1 William K. Schubert Professor of Pediatrics, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA Division of Developmental Biology, Cincinnati Children’s Hospital Medical Center, University of Cincinnati College of Medicine, Cincinnati, OH, USA 1 Corresponding author: e-mail address: [email protected]
Abstract In this assay, Raphael Kopan argues that focused emphasis on disease and translation stifles innovation, and outline the reasons why, in my opinion, developmental biologists are more likely to produce new and important discoveries than their more "focused" colleagues.
We are celebrating the 50th anniversary of Current Topics in Developmental Biology, started by Drs. Aaron A. Moscona and Alberto Monroy. I had the unique privilege to have been mentored by the late Aaron Moscona, bringing with it the opportunity to spend valuable time with him and his wife Malka, both of whom were exceptional developmental biologists, teachers, and colleagues. They are responsible for transforming my budding fascination in Developmental Biology into a life-long pursuit. It is highly appropriate therefore to contribute this essay in part to commemorate one of the founding editors of this series. In the last 50 years, we have seen our field ascend to a peak with the elucidation of the mechanisms underlying the major signaling pathways, a fundamental understanding of the genetic pathways regulating pattern formation, which was recognized by the 1995 Nobel Prize in Physiology or Medicine to Edward (Ed) Lewis, Christian ( Janni) Nusslein-Volhrd, and Eric Wieschaus, and the seminal work of John Gurdon, who laid the foundation to one of the most transformative discoveries of the twenty-first century, induced pluripotency (shared 2012 Nobel Prize in Physiology or Medicine with Dr. Shinya Yamanaka). Sadly, by that time, many Current Topics in Developmental Biology, Volume 116 ISSN 0070-2153 http://dx.doi.org/10.1016/bs.ctdb.2015.10.007
#
2016 Elsevier Inc. All rights reserved.
547
548
Raphael Kopan
developmental biologists interested in stem cells defected to create their own specialized discipline, publications, and meetings. This latest blow together with the overall decline in funding driven by the blunted, short-sighted vision of Congress and thus, the NIH, are the most important factors in the present state of our beloved discipline driving students and postdocs away. But, why should we care? Isn’t the “wisdom” of group science and disease focus self-evident? Developmental biologists are generalists. To paraphrase Sydney Brenner, I see developmental biologists as retaining a working multidimensional zoom, allowing them to travel in scale and in time and through any appropriate model organism, to continually convert original observations into discoveries of unexpected new mechanisms with relevance ranging from basic biological mechanisms to human disease. In this analogy, cell biologists rarely zoom up to the organ and the organism levels, while the stem-cell biologist are not always interested to zoom forward in time to look at the differentiated cells or organ. A stem cell biologist may look at stem cell aging only as an obstacle limiting the function of a perfect regenerative engine. In contrast, a developmental biologist would consider stem cell aging as a component in a complex developmental program that matches lifespan with the mode of reproduction (sexual vs. asexual), reproductive strategy (K vs. R), and niche availability. Only developmental biologists with a working zoom lens and a self-issued license to ponder any and all of these subjects, would consider all of them fair game. Perhaps I convinced you that this analogy has some merit, or perhaps not. Yet you wonder—so what? What is the advantage of a working multidimensional zoom? This seems so unfocused, slow, and counterproductive. We live in an era with heroes driven by focused, fast paced progress. Fixing on stem cells or neurons or T-cells only accelerates our ability to translate, utilize, commoditize, and monetize. True, but focus comes at a price. It reduces our ability to innovate. Innovation occurs in our peripheral vision, and only if we are willing (or feel entitled to do so because we are developmental biologists) to avert our gaze from the target and explore that observational flicker. Sure enough, it slows progress towards the target. But, it increases our chance to experience serendipity. Horace Walpole coined this term in 1754 to describe those “always making discoveries, by accidents and sagacity, of things which they were not in quest of.” Things you are not in quest of? So unfocused. Serendipity gets us involved in areas where we lack expertise, amplifying its benefits. Again paraphrasing Sydney Brenner, this allows one to
The Unaimed Arrow Never Misses
549
re-embrace one’s ignorance, to use it as a sharp scalpel, to think outside the box and ask “stupid” questions. Ignorance was instrumental in my own work on Notch signaling. I simply did not know anything about how signals were supposed to be propagated, and I worked with a mentor (the late Harold Weintraub) that felt no need to educate me on that point, allowing instead for the experimental path I took to unfold as it may. I learned first hand that when we apply a rigorous scientific method, and keep an open mind, we can make important discoveries we were not in the quest of: my target in those early days was to find genes involved in hair follicle development (Kopan & Weintraub, 1993). Residual Notch expression in the presomitic mesoderm (unrelated to hair biology) lead to an assay, which lead to the observation that active Notch constructs that could repress myogenesis had to reside in the nucleus, that lead to the hypothesis that Notch somehow had to get there in order to function, and so on. Of the many examples I can choose, lets consider how RNAi was discovered. The use of antisense DNA or RNA was commonplace at the time Kenneth Kemphues was investigating the PAR genes. However, Su Guo and Kemphues were the first to note the absence of strand specificity and the effectiveness of dsRNA in gene silencing (Guo & Kemphues, 1995). That was not what they were in the quest of, but they reported it anyway. The significance of this sidebar was not lost on a pair of developmental biologists, Drs. Craig Mello and Andrew Fire, already distracted from their respective quests by peripheral observations. As Dr. Mello recalled1: “The power of this gene-silencing approach accelerated our studies and we began to make rapid progress in understanding the developmental mechanisms that specify cell fate in the early embryo. However, we also became interested in the silencing phenomenon itself. The first observation that truly galvanized my interest occurred when, having injected RNA targeting apx-1, a gene essential for embryogenesis, I observed by chance that some embryos hatched and matured to adulthood only to produce 100% apx-1 dead embryos. The silencing phenomenon had skipped a generation and had been passed on via the germline to the next generation! This was truly amazing and prompted further studies that demonstrated the transmission of silencing for multiple generations via both the sperm and the egg… discovered, in part by accident while [a graduate student was] learning to inject…These findings, along with the inheritance properties, and the lack of strand specificity (first noted by Guo and Kemphues), prompted us to 1
http://www.nobelprize.org/nobel_prizes/medicine/laureates/2006/mello-bio.html.
550
Raphael Kopan
recognize the silencing phenomenon as an active response in the organism to the RNA.” This paragraph twice highlights the gravitational pull of a peripheral event, which combined with a prepared mind propelled these un-focused colleagues to a transformative discovery recognized by the award of the Nobel prize in Medicine, 2006, to Drs. Mello and Fire. The odds that a scientist with complete focus on human health would have discovered RNAi are minuscule. The larger the umbrella, the greater the opportunity we may engage in exploring things we were not in the quest of. I have gotten to the age when students decades younger than me lament that in my student years, discoveries were easier to come by (I confess to having the same concern learning about the birth of molecular biology (Weiner, 1999)). Now, they say, all the “good stuff” has been discovered. To that I reply: nonsense! We have only scratched the surface of what is yet to be discovered. Your problem is that you are too narrowly focused. Become a developmental biologist; claim all of life as your domain, and follow your peripheral vision.
ACKNOWLEDGMENTS The author wishes to thank Drs. Brian Gebelein, Kenny Campbell, Aaron Zorn, and Jeff Whitest for commenting on the chapter, and Tal Kopan, for expert advice and encouragement. R.K is supported by NIH RO1 GM55479.
REFERENCES Guo, S., & Kemphues, K. J. (1995). par-1, a gene required for establishing polarity in C. elegans embryos, encodes a putative Ser/Thr kinase that is asymmetrically distributed. Cell, 81, 611–620. Kopan, R., & Weintraub, H. (1993). Mouse notch: Expression in hair follicles correlates with cell fate determination. Journal of Cell Biology, 121, 631–641. Weiner, J. (1999). Time, love, memory: A great biologist and his quest for the origins of behavior. New York: Knopf.