- Email: [email protected]
Jody Rosenblatt
Current Biology
Magazine This conversion sacrifices color vision in favor of improved sensitivity in motion detection. Love spot R7s are modified in two main ways: first, they now respond to a broad spectrum instead of narrower ranges of color; and second, they connect to the motion-processing and spatial vision pathways of the brain — to the lamina instead of the medulla. This rewiring of the brain contributes one additional photoreceptor input per ommatidium toward motion processing and should in principle provide additional sensitivity, though perhaps as little as an 8% overall increase. It is possible that this additional sensitivity provides enough of an advantage to male Musca to be worth the loss of color vision across much of the visual field.
chasing mates could be useful here in both sexes; a sort of ‘killer spot’ used instead for predation. Farther away from the Muscidae, the eyes of dragonflies also show clear evidence of love spot-like features, with dorso-frontal eyes of both males and females exhibiting enlarged ommatidia and changes in pigmentation (Figure 1). Dragonflies are incredibly efficient flying predators. Both sexes also have specialized cells deeper in the brain that make use of motion vision information specifically from this modified region of the eye. It would be interesting to determine how the R7s are wired in the eyes of killer flies or in the specialized dorsal region of dragonflies, and to know which rhodopsins they express. Where can I find out more?
How else is the male visual system specialized for pursuit? Measurements using electrodes inserted into individual photoreceptors have shown that the love spot is 60% faster than female photoreceptors in the same region. These are actually some of the fastest recorded response times for any animal. This increase in speed may be the result of speeding up the biochemical processes involved in phototransduction, though the precise mechanisms are unknown. The ability of individual males to shoulder this additional metabolic cost and to sustain a strenuous chase may help indicate fitness to potential mates. In addition to having faster photoreceptors, specialized male-specific processing neurons have been identified deeper in the optic lobes. Large, tree-like lobula plate tangential neurons function to integrate motion input from across the visual field and relay this information to the central brain. Additional neurons of this type have been characterized in Musca males in regions corresponding to input from the love spot. The special focus on this region of the visual field apparently extends to higher-level processing in the brain. Could these specializations for extreme motion sensitivity and target tracking be useful in other contexts? Possibly, yes. Another species in the Musca family (Muscidae) is known as the ‘killer fly’, Coenosia tigrina. This predatory species sits and waits for prey to fly by. They are especially attentive to motion across the visual field in both males and females. Perhaps adaptations used for
Cronin, T.W., Johnsen, S., Marshall, N.J., and Warrant, E.J. (2014). Visual Ecology. (Princeton University Press.) Franceschini, N., Hardie, R., Ribi, W., and Kirschfeld, K. (1981). Sexual dimorphism in a photoreceptor. Nature 291, 241–244. Gonzalez-Bellido, P.T., Wardill, T.J., and Juusola, M. (2011). Compound eyes and retinal information processing in miniature dipteran species match their specific ecological demands. Proc. Natl. Acad. Sci. USA 108, 4224–4229. Hardie, R.C., Franceschini, N., Ribi, W., and Kirschfeld, K. (1981). Distribution and properties of sex-specific photoreceptors in the fly Musca domestica. J. Comp. Physiol. A. 145,139–152. Hardie, R.C. (1983). Projection and connectivity of sex-specific photoreceptors in the compound eye of the male housefly (Musca domestica). Cell Tissue Res. 233, 1–21. Hardie, R.C. (1985). Functional organization of the fly retina. In Progress in Sensory Physiology, volume 5, Autrum, H., Ottoson D., Perl, E.R., Schmidt, R.F., Shimazu, H., and Willis, W.D. (eds.). (Springer Berlin Heidelberg). Hardie, R.C. (1986). The photoreceptor array of the dipteran retina. Trends Neurosci. 9, 419–423. Hornstein, E.P., O’Carroll, D.C., Anderson, J.C., and Laughlin, S.B. (2000). Sexual dimorphism matches photoreceptor performance to behavioural requirements. Proc. Biol. Sci. 267, 2111–2117. Labhart, T., and Nilsson, D.-E. (1995). The dorsal eye of the dragonfly Sympetrum: specializations for prey detection against the blue sky. J. Comp. Physiol. A 176. 437–453. Land, M.F., and Nilsson, D.-E. (2012). Animal Eyes. (Oxford University Press). Strausfeld, N.J. (1991). Structural organization of male-specific visual neurons in calliphorid optic lobes. J. Comp. Physiol. A 169, 379–393. Warrant, E., and Nilsson, D.-E. (2006). Invertebrate Vision. (Cambridge University Press). Wernet, M.F., Perry, M.W., and Desplan, C. (2015). The evolutionary diversity of insect retinal mosaics: common design principles and emerging molecular logic. Trends Genet. 31, 316–328. Zeil, J. (1983). Sexual dimorphism in the visual system of flies: The compound eyes and neural superposition in bibionidae (Diptera). J. Comp. Physiol. A 150, 379–393.
Department of Biology, 100 Washington Square East, 1009 Silver Center, New York University, New York, NY 10003, USA. E-mail: [email protected],(M.W.P); [email protected] (C.D.)
Q&A
Jody Rosenblatt Jody Rosenblatt is an Associate Professor in the Oncological Sciences Department at the University of Utah and an Investigator at the Huntsman Cancer Institute. She earned a B.A. from the University of California, Berkeley and a Ph.D. from the University of California, San Francisco, working with Tim Mitchison. Following post-doctoral work with Martin Raff and Louise Cramer at the Laboratory for Molecular Cell Biology at University College London, she set up her own lab in 2005 in her native Utah. Her lab studies how mechanical forces control epithelial cell numbers through a novel mechanism called ‘epithelial cell extrusion’ that drives cell death while allowing epithelia to maintain a constant barrier. How did you first become interested in biology? When I was young, I did field trips to our Natural History Museum where we did science experiments. I loved this! But I never thought I could do this as a career — even years later when I went to university. My good friend Pam said ‘she wanted to be a rad scientist and cure cancer’. I remember thinking ‘and I want to become a fairy’ — something I thought equally unreal. As I went on, though, I realized that fantasy could become a reality and I sometimes still marvel that I get to do what I do for a living. Because of the impact the museum had on me, we now invite school students to do experiments in our lab every year. Hopefully, this gives them an opportunity to see science not just as facts in a textbook but a process to discover things that no one else has seen before. How did you become interested in cancer biology? This interest evolved from my primary interest in how epithelia control cell turnover. Epithelial cells must work collectively to form a tight barrier for all the organs they encase, yet they turnover by cell death and division at some of the fastest rates in the body. The number of cells that die must match those that divide, otherwise epithelia
Current Biology 26, R481–R492, June 20, 2016
R485
Current Biology
Magazine not actually committing suicide but were instead being extruded by their neighboring cells. These cells would then die by a type of apoptosis that occurs only from loss of survival signaling or anoikis. The discovery that most epithelial cells are extruded while they are still actually alive suggests that extrusion drives epithelial cell death during homeostatic turnover. The fact that this process is hijacked to drive tumor formation and invasion is testament to its importance in controlling cell death.
would lose their function as a barrier or cancers (90% of which arise from simple epithelia) might form. My lab has found that mechanical tension controls this balance by regulating both cell death and division through a single stretch-activated protein. It is actually quite simple: when cells become too sparse, mechanical stretch within the cell rapidly activates its division, when they become too overpopulated, crowding tension drives cells to extrude and then die. From our discovery of epithelial cell extrusion and the signaling mechanism that controls it, we found that this mechanism is disrupted in many types of aggressive tumors. Disrupting extrusion causes cells to pile up where they would normally be extruded, but they also cause cells to escape via a sneakier path, underneath the epithelium. We are now thinking that this aberrant, basal extrusion is how tumor cells can start to invade the underlying tissue and begin to metastasize. How did you discover extrusion? Like most discoveries, by accident. I had gone to London for my postdoc to study wound healing. But, when I was trying to watch wounds close that I had made in chick and mouse embryonic epithelia, I kept getting distracted by lots of small singlecelled wounds that I hadn’t made. These were cells being extruded. Initially, we had assumed that these cells were apoptotic. It was only later that we found that they were R486
You’ve now based most of the work in your lab on extrusion. Did your discovery of extrusion make it easy for you to get a job and funding? No, not really. While our work on extrusion is rapidly expanding into a variety of areas that impact cancer, asthma and potentially vascular diseases, I actually got more traction for my job search from a side project on the role that actin and myosin play in spindle assembly. The work on extrusion was published in one of my favorite journals (Current Biology!) but the findings did not fit into a field exactly and were somehow harder for people to wrap their heads around. However, the findings we’ve had on extrusion were more fundamental and have led to related research in a vast array of research in development, bacterial pathogenesis, inflammatory diseases and cancer, so I knew that extrusion was where we should focus. Getting funding in a new area was more difficult, but I was blessed by two funding mechanisms. The first were two project grants (from Cancer Research UK and the Biotechnology and Biological Research Society Council (BBSRC)) that I was granted as a post-doc in the UK — enough to fund another post-doc and myself. These were critical for me to get work started in this new area and I am very sad to hear that they are phasing out this type of grant now. The beauty of these schemes was that the administrative and reviewer burden was low and, because they did not award too much money, they could take higher risks. When I came back to the US, the traditional funding schemes — RO1s — were much more conservative and cautious. They
Current Biology 26, R481–R492, June 20, 2016
expect you to have several papers already and much of the data in hand. This makes it very hard to try new things. Luckily, I eventually got funded through a new mechanism that was designed for early researchers who are working on new ideas — the NIH Director’s New Innovator Award. This saved my scientific career and allowed me to get the papers under my belt expected for the more traditional mechanisms. So, would you say that the US needs different types of funding mechanism? Absolutely! I’m glad that you asked that question. Since I returned to the US as an independent investigator I’ve been noticing not only a growing separation between the rich and poor in the country but also between the rich and poor in science. Looking at analyses from the NIH, I see that half of all the funding goes to awards of $2–64 million! It seems unlikely that these labs or consortia could be 4–250 times more productive than a lab that has the equivalent of only one to two RO1 grants. This inequality suggests that we need a kind of Bernie Sanders in science! I’ve noticed how much easier it is for wealthy labs to get more funding and papers whereas colleagues with smaller labs are facing the likelihood of being cut off entirely. This growing separation is not only pushing out valued colleagues but it is also eliminating new ideas from blossoming. And, you never know where the next breakthrough idea will come from. Recombinant DNA and CRISPR technologies are testament to this. In the cancer field, I often say, if there were a prescribed way to cure cancer, we would have cured all cancers. The recent breakthrough in immunotherapy, for instance, is derived from Jim Allison’s interest in how the T-cell response becomes downregulated, which was a basic biological question. Also from our understanding of a basic cell biological problem — how do epithelial cells normally die? — compelling leads have emerged on how to treat a class of very aggressive cancers. How could we fix these funding problems then? Of all countries, the
Current Biology
Magazine US spends the most on science. Yet, I have colleagues that were told that they wouldn’t get their grant after scoring in the top eight percent! I was very disturbed by a key point that we were required to consider for scoring fellowships on a study section recently; did the mentor have funding that spanned the entire projected time of the post-doc or student’s grant? If not, they were excluded. This sort of gaming the system makes it inevitable that labs with already sufficient money have an edge on getting more funding and trainees. Ultimately, this will also result in trainees coming from fewer and narrower ranges of research. Aside from eliminating these restrictive modes of funding, I would advocate developing similar granting schemes such as the ones I obtained as a post-doc: short grants that fund less and could, therefore, be more risk-taking. This would simultaneously keep the smaller labs afloat and keep all the newly built science buildings full. It would take less time to write such grants and review them, which consumes so much of the modern scientist’s time. I also agree with Frederick Grinnell that in grant awards, we could move to a winner-takes-some rather than a winner-takes-all scenario, where grants with lower scores could be awarded less to get them going while the top-ranking grants earn more. Additionally, in the same way that our dean, Vivian Lee, has lead the country in examining cost-cutting measures in clinical treatment that yield the same outcomes, we should have a similar analysis in real output per dollar of funding. Typically, beyond $750K per year, labs do not increase their productivity, as measured by papers and patents. Thus, labs with funding above this amount should be held to far higher scrutiny and accountability in their output and novel findings. Finally, we need to advocate for basic research, as so many of the translational outcomes that have benefited the public have stemmed fundamentally from basic findings with no initial clinical goal. Huntsman Cancer Institute, Oncological Sciences Dept, University of Utah, Salt Lake City, UT 84112, USA. E-mail: [email protected]
Primer
Centromeres Lisa E. Kursel1 and Harmit S. Malik2,3,* Centromeres, chromosomal regions that become physically linked to the spindle during cell division, ensure equal division of genetic material between daughter cells. They are ubiquitous and essential in eukaryotic life. In this primer, we ask the questions ‘What defines a functional centromere?’ and ‘What do all centromeres have in common?’ To address these questions we highlight what is known about centromere size, centromere architecture, underlying DNA sequence and centromeric proteins. Studies from a variety of organisms reveal a vast diversity in centromere form and function that remains perplexing and largely unexplained. The significance of centromeres Omnis cellula e cellula: all cells come from cells. By the mid-19th century, scientists had rejected the notion that organisms could spontaneously arise from non-living matter, and agreed that cells divided to form new cells. By the end of the 19th century, the process of mitosis had been described through direct cytological observations; chromosomes (‘colored bodies’) in the nucleus were recognized as the supplier of genetic material. Experiments carried out by Theodor Boveri in sea urchin embryos demonstrated that cells required a full set of chromosomes for development; having too many or too few chromosomes (aneuploidy) caused developmental defects. But how do eukaryotic cells orchestrate the exact partitioning of chromosomes to daughter cells? Centromeres are the key. Centromeres were first described by Walther Flemming in 1882 as the primary constrictions on chromosomes to which fibers emanating from the spindle made physical connections. By the early 1900s, centromeres had acquired a genetic definition: the sites on a chromosome responsible for its inheritance. Budding yeast centromeres make a point How are centromeres specified on a chromosome? Louise Clarke
and John Carbon were the first to genetically characterize centromeres, in the budding yeast Saccharomyces cerevisiae (Figure 1A). They identified centromere-linked genes on both sides of S. cerevisiae chromosome III, and then ‘walked’ along the chromosome between the centromere-linked genes, using a technique called overlaphybridization, to map the entire region. Finally, they were able to identify centromeric sequences, which were capable of conferring mitotic and meiotic stability on a replicating plasmid upon insertion. They concluded that the centromeric DNA sequences must, therefore, specify the centromeres on budding yeast chromosomes. A subsequent screen assayed fragmented pieces of the S. cerevisiae genome for their ability to confer mitotic stability on plasmids. This screen identified several such sequences, eventually identifying one 120 bp (termed the CEN, for centromeric) sequence per S. cerevisiae chromosome. Additional experiments showed that these sequences were both necessary and sufficient to mediate chromosome segregation in S. cerevisiae; i.e. it represented a genetically defined ‘point’ centromere. The CEN sequence was later shown to be capable of mediating assembly of a multiprotein complex, termed the kinetochore, which provides the connection between the chromosomal centromere and microtubules to mediate proper chromosome segregation. Centromeres go regional Studies outside of budding yeasts have shown that the short, genetic centromeres of S. cerevisiae and its relatives are an exception, not the rule (Table 1). In other organisms, centromeres are much larger and often made up of repetitive DNA. In the fission yeast Schizosaccharomyces pombe, the minimum chromosomal segment that is capable of high-fidelity mitotic and meiotic segregation was found to be 35–50 kilobases long, with a 3–5 kb non-repetitive, AT-rich central core flanked by repetitive elements. Subsequent studies suggested that while only the non-repetitive central core recruits kinetochores, the flanking repeats recruit additional non-centromeric proteins (e.g.,
Current Biology 26, R481–R492, June 20, 2016 © 2016 Elsevier Ltd. R487
Magazine This conversion sacrifices color vision in favor of improved sensitivity in motion detection. Love spot R7s are modified in two main ways: first, they now respond to a broad spectrum instead of narrower ranges of color; and second, they connect to the motion-processing and spatial vision pathways of the brain — to the lamina instead of the medulla. This rewiring of the brain contributes one additional photoreceptor input per ommatidium toward motion processing and should in principle provide additional sensitivity, though perhaps as little as an 8% overall increase. It is possible that this additional sensitivity provides enough of an advantage to male Musca to be worth the loss of color vision across much of the visual field.
chasing mates could be useful here in both sexes; a sort of ‘killer spot’ used instead for predation. Farther away from the Muscidae, the eyes of dragonflies also show clear evidence of love spot-like features, with dorso-frontal eyes of both males and females exhibiting enlarged ommatidia and changes in pigmentation (Figure 1). Dragonflies are incredibly efficient flying predators. Both sexes also have specialized cells deeper in the brain that make use of motion vision information specifically from this modified region of the eye. It would be interesting to determine how the R7s are wired in the eyes of killer flies or in the specialized dorsal region of dragonflies, and to know which rhodopsins they express. Where can I find out more?
How else is the male visual system specialized for pursuit? Measurements using electrodes inserted into individual photoreceptors have shown that the love spot is 60% faster than female photoreceptors in the same region. These are actually some of the fastest recorded response times for any animal. This increase in speed may be the result of speeding up the biochemical processes involved in phototransduction, though the precise mechanisms are unknown. The ability of individual males to shoulder this additional metabolic cost and to sustain a strenuous chase may help indicate fitness to potential mates. In addition to having faster photoreceptors, specialized male-specific processing neurons have been identified deeper in the optic lobes. Large, tree-like lobula plate tangential neurons function to integrate motion input from across the visual field and relay this information to the central brain. Additional neurons of this type have been characterized in Musca males in regions corresponding to input from the love spot. The special focus on this region of the visual field apparently extends to higher-level processing in the brain. Could these specializations for extreme motion sensitivity and target tracking be useful in other contexts? Possibly, yes. Another species in the Musca family (Muscidae) is known as the ‘killer fly’, Coenosia tigrina. This predatory species sits and waits for prey to fly by. They are especially attentive to motion across the visual field in both males and females. Perhaps adaptations used for
Cronin, T.W., Johnsen, S., Marshall, N.J., and Warrant, E.J. (2014). Visual Ecology. (Princeton University Press.) Franceschini, N., Hardie, R., Ribi, W., and Kirschfeld, K. (1981). Sexual dimorphism in a photoreceptor. Nature 291, 241–244. Gonzalez-Bellido, P.T., Wardill, T.J., and Juusola, M. (2011). Compound eyes and retinal information processing in miniature dipteran species match their specific ecological demands. Proc. Natl. Acad. Sci. USA 108, 4224–4229. Hardie, R.C., Franceschini, N., Ribi, W., and Kirschfeld, K. (1981). Distribution and properties of sex-specific photoreceptors in the fly Musca domestica. J. Comp. Physiol. A. 145,139–152. Hardie, R.C. (1983). Projection and connectivity of sex-specific photoreceptors in the compound eye of the male housefly (Musca domestica). Cell Tissue Res. 233, 1–21. Hardie, R.C. (1985). Functional organization of the fly retina. In Progress in Sensory Physiology, volume 5, Autrum, H., Ottoson D., Perl, E.R., Schmidt, R.F., Shimazu, H., and Willis, W.D. (eds.). (Springer Berlin Heidelberg). Hardie, R.C. (1986). The photoreceptor array of the dipteran retina. Trends Neurosci. 9, 419–423. Hornstein, E.P., O’Carroll, D.C., Anderson, J.C., and Laughlin, S.B. (2000). Sexual dimorphism matches photoreceptor performance to behavioural requirements. Proc. Biol. Sci. 267, 2111–2117. Labhart, T., and Nilsson, D.-E. (1995). The dorsal eye of the dragonfly Sympetrum: specializations for prey detection against the blue sky. J. Comp. Physiol. A 176. 437–453. Land, M.F., and Nilsson, D.-E. (2012). Animal Eyes. (Oxford University Press). Strausfeld, N.J. (1991). Structural organization of male-specific visual neurons in calliphorid optic lobes. J. Comp. Physiol. A 169, 379–393. Warrant, E., and Nilsson, D.-E. (2006). Invertebrate Vision. (Cambridge University Press). Wernet, M.F., Perry, M.W., and Desplan, C. (2015). The evolutionary diversity of insect retinal mosaics: common design principles and emerging molecular logic. Trends Genet. 31, 316–328. Zeil, J. (1983). Sexual dimorphism in the visual system of flies: The compound eyes and neural superposition in bibionidae (Diptera). J. Comp. Physiol. A 150, 379–393.
Department of Biology, 100 Washington Square East, 1009 Silver Center, New York University, New York, NY 10003, USA. E-mail: [email protected],(M.W.P); [email protected] (C.D.)
Q&A
Jody Rosenblatt Jody Rosenblatt is an Associate Professor in the Oncological Sciences Department at the University of Utah and an Investigator at the Huntsman Cancer Institute. She earned a B.A. from the University of California, Berkeley and a Ph.D. from the University of California, San Francisco, working with Tim Mitchison. Following post-doctoral work with Martin Raff and Louise Cramer at the Laboratory for Molecular Cell Biology at University College London, she set up her own lab in 2005 in her native Utah. Her lab studies how mechanical forces control epithelial cell numbers through a novel mechanism called ‘epithelial cell extrusion’ that drives cell death while allowing epithelia to maintain a constant barrier. How did you first become interested in biology? When I was young, I did field trips to our Natural History Museum where we did science experiments. I loved this! But I never thought I could do this as a career — even years later when I went to university. My good friend Pam said ‘she wanted to be a rad scientist and cure cancer’. I remember thinking ‘and I want to become a fairy’ — something I thought equally unreal. As I went on, though, I realized that fantasy could become a reality and I sometimes still marvel that I get to do what I do for a living. Because of the impact the museum had on me, we now invite school students to do experiments in our lab every year. Hopefully, this gives them an opportunity to see science not just as facts in a textbook but a process to discover things that no one else has seen before. How did you become interested in cancer biology? This interest evolved from my primary interest in how epithelia control cell turnover. Epithelial cells must work collectively to form a tight barrier for all the organs they encase, yet they turnover by cell death and division at some of the fastest rates in the body. The number of cells that die must match those that divide, otherwise epithelia
Current Biology 26, R481–R492, June 20, 2016
R485
Current Biology
Magazine not actually committing suicide but were instead being extruded by their neighboring cells. These cells would then die by a type of apoptosis that occurs only from loss of survival signaling or anoikis. The discovery that most epithelial cells are extruded while they are still actually alive suggests that extrusion drives epithelial cell death during homeostatic turnover. The fact that this process is hijacked to drive tumor formation and invasion is testament to its importance in controlling cell death.
would lose their function as a barrier or cancers (90% of which arise from simple epithelia) might form. My lab has found that mechanical tension controls this balance by regulating both cell death and division through a single stretch-activated protein. It is actually quite simple: when cells become too sparse, mechanical stretch within the cell rapidly activates its division, when they become too overpopulated, crowding tension drives cells to extrude and then die. From our discovery of epithelial cell extrusion and the signaling mechanism that controls it, we found that this mechanism is disrupted in many types of aggressive tumors. Disrupting extrusion causes cells to pile up where they would normally be extruded, but they also cause cells to escape via a sneakier path, underneath the epithelium. We are now thinking that this aberrant, basal extrusion is how tumor cells can start to invade the underlying tissue and begin to metastasize. How did you discover extrusion? Like most discoveries, by accident. I had gone to London for my postdoc to study wound healing. But, when I was trying to watch wounds close that I had made in chick and mouse embryonic epithelia, I kept getting distracted by lots of small singlecelled wounds that I hadn’t made. These were cells being extruded. Initially, we had assumed that these cells were apoptotic. It was only later that we found that they were R486
You’ve now based most of the work in your lab on extrusion. Did your discovery of extrusion make it easy for you to get a job and funding? No, not really. While our work on extrusion is rapidly expanding into a variety of areas that impact cancer, asthma and potentially vascular diseases, I actually got more traction for my job search from a side project on the role that actin and myosin play in spindle assembly. The work on extrusion was published in one of my favorite journals (Current Biology!) but the findings did not fit into a field exactly and were somehow harder for people to wrap their heads around. However, the findings we’ve had on extrusion were more fundamental and have led to related research in a vast array of research in development, bacterial pathogenesis, inflammatory diseases and cancer, so I knew that extrusion was where we should focus. Getting funding in a new area was more difficult, but I was blessed by two funding mechanisms. The first were two project grants (from Cancer Research UK and the Biotechnology and Biological Research Society Council (BBSRC)) that I was granted as a post-doc in the UK — enough to fund another post-doc and myself. These were critical for me to get work started in this new area and I am very sad to hear that they are phasing out this type of grant now. The beauty of these schemes was that the administrative and reviewer burden was low and, because they did not award too much money, they could take higher risks. When I came back to the US, the traditional funding schemes — RO1s — were much more conservative and cautious. They
Current Biology 26, R481–R492, June 20, 2016
expect you to have several papers already and much of the data in hand. This makes it very hard to try new things. Luckily, I eventually got funded through a new mechanism that was designed for early researchers who are working on new ideas — the NIH Director’s New Innovator Award. This saved my scientific career and allowed me to get the papers under my belt expected for the more traditional mechanisms. So, would you say that the US needs different types of funding mechanism? Absolutely! I’m glad that you asked that question. Since I returned to the US as an independent investigator I’ve been noticing not only a growing separation between the rich and poor in the country but also between the rich and poor in science. Looking at analyses from the NIH, I see that half of all the funding goes to awards of $2–64 million! It seems unlikely that these labs or consortia could be 4–250 times more productive than a lab that has the equivalent of only one to two RO1 grants. This inequality suggests that we need a kind of Bernie Sanders in science! I’ve noticed how much easier it is for wealthy labs to get more funding and papers whereas colleagues with smaller labs are facing the likelihood of being cut off entirely. This growing separation is not only pushing out valued colleagues but it is also eliminating new ideas from blossoming. And, you never know where the next breakthrough idea will come from. Recombinant DNA and CRISPR technologies are testament to this. In the cancer field, I often say, if there were a prescribed way to cure cancer, we would have cured all cancers. The recent breakthrough in immunotherapy, for instance, is derived from Jim Allison’s interest in how the T-cell response becomes downregulated, which was a basic biological question. Also from our understanding of a basic cell biological problem — how do epithelial cells normally die? — compelling leads have emerged on how to treat a class of very aggressive cancers. How could we fix these funding problems then? Of all countries, the
Current Biology
Magazine US spends the most on science. Yet, I have colleagues that were told that they wouldn’t get their grant after scoring in the top eight percent! I was very disturbed by a key point that we were required to consider for scoring fellowships on a study section recently; did the mentor have funding that spanned the entire projected time of the post-doc or student’s grant? If not, they were excluded. This sort of gaming the system makes it inevitable that labs with already sufficient money have an edge on getting more funding and trainees. Ultimately, this will also result in trainees coming from fewer and narrower ranges of research. Aside from eliminating these restrictive modes of funding, I would advocate developing similar granting schemes such as the ones I obtained as a post-doc: short grants that fund less and could, therefore, be more risk-taking. This would simultaneously keep the smaller labs afloat and keep all the newly built science buildings full. It would take less time to write such grants and review them, which consumes so much of the modern scientist’s time. I also agree with Frederick Grinnell that in grant awards, we could move to a winner-takes-some rather than a winner-takes-all scenario, where grants with lower scores could be awarded less to get them going while the top-ranking grants earn more. Additionally, in the same way that our dean, Vivian Lee, has lead the country in examining cost-cutting measures in clinical treatment that yield the same outcomes, we should have a similar analysis in real output per dollar of funding. Typically, beyond $750K per year, labs do not increase their productivity, as measured by papers and patents. Thus, labs with funding above this amount should be held to far higher scrutiny and accountability in their output and novel findings. Finally, we need to advocate for basic research, as so many of the translational outcomes that have benefited the public have stemmed fundamentally from basic findings with no initial clinical goal. Huntsman Cancer Institute, Oncological Sciences Dept, University of Utah, Salt Lake City, UT 84112, USA. E-mail: [email protected]
Primer
Centromeres Lisa E. Kursel1 and Harmit S. Malik2,3,* Centromeres, chromosomal regions that become physically linked to the spindle during cell division, ensure equal division of genetic material between daughter cells. They are ubiquitous and essential in eukaryotic life. In this primer, we ask the questions ‘What defines a functional centromere?’ and ‘What do all centromeres have in common?’ To address these questions we highlight what is known about centromere size, centromere architecture, underlying DNA sequence and centromeric proteins. Studies from a variety of organisms reveal a vast diversity in centromere form and function that remains perplexing and largely unexplained. The significance of centromeres Omnis cellula e cellula: all cells come from cells. By the mid-19th century, scientists had rejected the notion that organisms could spontaneously arise from non-living matter, and agreed that cells divided to form new cells. By the end of the 19th century, the process of mitosis had been described through direct cytological observations; chromosomes (‘colored bodies’) in the nucleus were recognized as the supplier of genetic material. Experiments carried out by Theodor Boveri in sea urchin embryos demonstrated that cells required a full set of chromosomes for development; having too many or too few chromosomes (aneuploidy) caused developmental defects. But how do eukaryotic cells orchestrate the exact partitioning of chromosomes to daughter cells? Centromeres are the key. Centromeres were first described by Walther Flemming in 1882 as the primary constrictions on chromosomes to which fibers emanating from the spindle made physical connections. By the early 1900s, centromeres had acquired a genetic definition: the sites on a chromosome responsible for its inheritance. Budding yeast centromeres make a point How are centromeres specified on a chromosome? Louise Clarke
and John Carbon were the first to genetically characterize centromeres, in the budding yeast Saccharomyces cerevisiae (Figure 1A). They identified centromere-linked genes on both sides of S. cerevisiae chromosome III, and then ‘walked’ along the chromosome between the centromere-linked genes, using a technique called overlaphybridization, to map the entire region. Finally, they were able to identify centromeric sequences, which were capable of conferring mitotic and meiotic stability on a replicating plasmid upon insertion. They concluded that the centromeric DNA sequences must, therefore, specify the centromeres on budding yeast chromosomes. A subsequent screen assayed fragmented pieces of the S. cerevisiae genome for their ability to confer mitotic stability on plasmids. This screen identified several such sequences, eventually identifying one 120 bp (termed the CEN, for centromeric) sequence per S. cerevisiae chromosome. Additional experiments showed that these sequences were both necessary and sufficient to mediate chromosome segregation in S. cerevisiae; i.e. it represented a genetically defined ‘point’ centromere. The CEN sequence was later shown to be capable of mediating assembly of a multiprotein complex, termed the kinetochore, which provides the connection between the chromosomal centromere and microtubules to mediate proper chromosome segregation. Centromeres go regional Studies outside of budding yeasts have shown that the short, genetic centromeres of S. cerevisiae and its relatives are an exception, not the rule (Table 1). In other organisms, centromeres are much larger and often made up of repetitive DNA. In the fission yeast Schizosaccharomyces pombe, the minimum chromosomal segment that is capable of high-fidelity mitotic and meiotic segregation was found to be 35–50 kilobases long, with a 3–5 kb non-repetitive, AT-rich central core flanked by repetitive elements. Subsequent studies suggested that while only the non-repetitive central core recruits kinetochores, the flanking repeats recruit additional non-centromeric proteins (e.g.,
Current Biology 26, R481–R492, June 20, 2016 © 2016 Elsevier Ltd. R487