NEWS & VIEWS RESEARCH numbers in the central nervous system of adult mice, or to block the pericyte’s ability to contract. Subsequent analysis of the changes in cerebral capillary blood flow induced by neuronal activity in these animals compared with controls would help to delineate a more precise role for pericytes in regulating blood flow in the brain. Ischaemic stroke, caused by a lack of blood to the brain, has devastating effects. Treatments are limited because reperfusion strategies that aim to restore blood supply are effective within only around 4.5 hours of the onset of symptoms. Treatment efficacy is limited by time because reperfusion is impaired when the reopening of a large artery is delayed (known as the no-reflow phenomenon). Although controversial, persistent pericyte contraction after ischaemia has been implicated as a cause of the no-reflow phenomenon in capillaries11,12. Hall and colleagues demonstrate that, on exposure of rat brain slices to conditions simulating ischaemia, capillaries constrict and then pericytes die (Fig. 1b). Furthermore, the authors found that in rats, temporary obstruction of a cerebral artery in vivo induces substantial death of pericytes, but not of endothelial
cells that make up the blood vessels. Hall and co-workers suggest that the longterm reduction of cerebral blood flow after reperfusion of a blocked artery may be at least partly attributable to pericyte rigor mortis — literally ‘the stiffness of death’ (Fig. 1c). In rigor mortis, stiffness results from a lack of ATP molecules, which prevents myosin and actin — two proteins that interact to cause muscle contraction — from being separated from one another. The concept of prolonged vasoconstriction due to strangulation by dead pericytes raises several questions that require further investigation. Why are pericytes, as opposed to other cell types such as endothelial cells, particularly susceptible to ischaemia-induced death? Can pericyte death be prevented, and will this inhibit the no-reflow phenomenon? Is pericyte rigor mortis a factor in this phenomenon after injury in other tissues, particularly in the heart following a heart attack? If this model of ischaemia-induced pericyte rigor mortis remains robust in the face of further analysis, it may pave the way for approaches to combat ischaemic injury that prevent pericyteinduced loss of a tissue’s ability to reperfuse. ■
P L AN ETARY SCIENCE
A chronometer for Earth’s age Simulations of Earth’s growth show a correlation between the timing of the Moon’s formation and the amount of mass that Earth accreted afterwards. This relationship provides a way of measuring the age of our planet. See Letter p.84 JOHN CHAMBERS
T
he age of the oldest objects in the Solar System is known with remarkable precision — 4,567 million years1,2 — thanks to recent strides in the dating of meteorites. Unfortunately, applying the same dating methods to Earth yields an age that is frustratingly fuzzy. Our planet formed sometime during the first 150 million years of the Solar System’s history3–5, but we do not know when. On page 84 of this issue, Jacobson et al.6 propose a way of measuring the time at which Earth finished forming using numerical simulations of the planet’s growth and its chemical composition. Their result: Earth formed in 95 million years, with an uncertainty of about 32–39 million years, making the planet about 4,470 million years old. A big part of the problem with dating Earth is that our planet did not appear overnight. Starting from humble beginnings, Earth gradually accumulated material over an extended
period of time. Indeed, it is still gaining mass today in the form of meteorites and interplanetary dust particles. What is needed is a milestone in Earth’s growth at which we can say that the planet was essentially complete. A widely adopted milestone is the major collision with a planet-sized body that is thought to have formed the Moon7 (Fig. 1). Current theory suggests that Earth experienced several of these ‘giant impacts’ during its formation, with the Moon-forming impact being the last. Each impact mixed together material that would end up in Earth’s metallic core and rocky mantle, as well as adding bulk to both. The prolonged nature of Earth’s growth and the existence of multiple giant impacts complicate the task of dating Earth using radiometric clocks — those that combine known decay rates of radioactive materials with measurements of how these materials and their decay products are distributed within Earth today. For one thing, it is unclear just how much mixing of core and mantle material occurred
Daniel M. Greif and Anne Eichmann are at the Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA. A.E. is also in the Department of Cellular and Molecular Physiology, Yale University School of Medicine, and at the Center for Interdisciplinary Research in Biology, Collège de France, Paris. e-mails: [email protected]; [email protected] 1. Hall, C. N. et al. Nature 508, 55–60 (2014). 2. Rouget, C. Arch. Physiol. Normal Pathol. 5, 603–663 (1873). 3. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Nature 468, 562–566 (2010). 4. Armulik, A. et al. Nature 468, 557–561 (2010). 5. Bell, R. D. et al. Neuron 68, 409–427 (2010). 6. Bell, R. D. et al. Nature 485, 512–516 (2012). 7. Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J. & Lindauer, U. Proc. Natl Acad. Sci. USA 107, 22290–22295 (2010). 8. Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Nature 443, 700–704 (2006). 9. Cohen, Z., Molinatti, G. & Hamel, E. J. Cereb. Blood Flow Metab. 17, 894–904 (1997). 10. Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Science 277, 242–245 (1997). 11. Yemisci, M. et al. Nature Med. 15, 1031–1037 (2009). 12. Vates, G. E., Takano, T., Zlokovic, B. & Nedergaard, M. Nature Med. 16, 959 (2010). This article was published online on 26 March 2014.
with each giant impact, and to what extent the radiometric clocks were reset as a result. Earth probably retains a memory of several of these events, rather than just the last one. Giant impacts may have ejected some of the planet’s more volatile elements into space, distorting radiometric dating systems that assume that all of the radioactive decay products are still present. It is also possible that Earth’s core and mantle continued to interact for some time after the last giant impact. This is where modelling the growth of our planet could pay dividends. The formation of the Sun’s rocky planets probably passed through several stages 8, beginning with micrometre-sized dust grains in the nascent Solar System, proceeding to asteroid-sized bodies known as planetesimals, and then to a few dozen Moon-to-Mars-mass planetary embryos. The accumulation of these planetary embryos into the modern rocky planets through occasional giant impacts was by far the slowest stage, and it largely determined how long Earth took to form. Jacobson et al. have modelled this final growth stage, beginning with various populations of planetary embryos and planetesimals. They also examined two widely different scenarios for what the giant planets of the Solar System were doing during this time. En route, the authors found an interesting and remarkably robust correlation: the timing of the last giant impact on Earth is inversely related to the amount of mass the planet accumulated afterwards from leftover planetesimals. If the last giant impact occurred early on, there would have been plenty of planetesimals left 3 A P R I L 2 0 1 4 | VO L 5 0 8 | NAT U R E | 5 1
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS NASA
planets orbiting very close to their star11. If conditions during the growth of the planets were different from those assumed by Jacobson et al., then the authors’ estimated age for Earth could be incorrect. Despite this caveat, it is encouraging to see studies that combine the fundamental physics inherent in numerical simulations of planet formation with the wealth of information available on Earth’s composition. Understanding how and when the Sun’s planets formed is immensely challenging, and researchers need every tool available. Studies such as the one by Jacobson and colleagues may be the best hope for understanding how and when our planet came to be. ■ John Chambers is in the Department of Terrestrial Magnetism, Carnegie Institution for Science, Washington DC 20015, USA. e-mail: [email protected]
Figure 1 | Earthrise from the Moon. Jacobson et al.6 find that the timing of the Moon-forming impact on Earth is inversely related to the amount of mass that the planet accumulated afterwards.
for Earth to sweep up afterwards. If the last giant impact was late, few planetesimals would have remained, and Earth’s growth would have largely ceased. This correlation provides an independent way of dating the Moon-forming impact, provided that we can measure the amount of material that arrived subsequently. Fortunately, there is a way to do this. Several elements, such as iridium and platinum, show a strong tendency to move into Earth’s core. During the upheaval of each giant impact, these elements leached from the planet’s mantle, bonding with heavy, iron-rich material destined to sink to the core. After the last giant impact, Earth’s mantle should have been almost completely stripped of iridium,platinum and their cousins. In practice, these elements are present in small amounts in the mantle, and in the same relative proportions seen in many meteorites9. To many researchers, this suggests that Earth acquired a fraction of its mass after the last giant impact, when the core and mantle had ceased separating. Jacobson et al. combine the measured mass of this extra material with the correlation from their simulations to date the Moon-forming impact and then deduce Earth’s age. They find it very unlikely that Earth finished forming in the first 38 million years of the Solar System. Their favoured time — 95 million years — is compatible with some radiometric-dating estimates for when Earth’s core finished forming4, and makes Earth comfortably older than the oldest minerals known to have formed in its crust10.
Naturally, Jacobson and colleagues’ method is only as valid as our picture of how planets form. The standard model for planet formation in the Solar System is far from complete, and it has had a torrid time lately trying to explain some aspects of extrasolar planetary systems, such as the existence of Earth-sized
1. Amelin, Y. et al. Earth Planet. Sci. Lett. 300, 343–350 (2010). 2. Connelly, J. N. et al. Science 338, 651–655 (2012). 3. Yin, Q. et al. Nature 418, 949–952 (2002). 4. Allègre, C. J., Manhès, G. & Göpel, C. Earth Planet. Sci. Lett. 267, 386–398 (2008). 5. Halliday, A. N. Phil. Trans. R. Soc. A 366, 4163–4181 (2008). 6. Jacobson, S. A. et al. Nature 508, 84–87 (2014). 7. Canup, R. M. & Asphaug, E. Nature 412, 708–712 (2001). 8. Morbidelli, A., Lunine, J. I., O’Brien, D. P., Raymond, S. N. & Walsh, K. J. Annu. Rev. Earth Planet. Sci. 40, 251–275 (2012). 9. Walker, R. J. Chem. Erde Geochem. 69, 101–125 (2009). 10. Valley, J. W. et al. Nature Geosci. 7, 219–223 (2014). 11. Dong, S. & Zhu, Z. Astrophys. J. 778, 53 (2013).
CA N C ER
Clonal cooperation Widespread genetic heterogeneity in cells of human tumours poses a question: what prevents the fittest clone from taking over? A demonstration of interdependence between distinct clones might shed light on this puzzle. See Letter p.113 K O R N E L I A P O LYA K & A N D R I Y M A R U S Y K
S
equencing of human cancer genomes has revealed a high degree of genetic heterogeneity among cells of a given tumour1. In most cases, tumour growth is thought to be driven by the most ‘advanced’ cancer-cell subpopulation — that carrying the highest number of cancer-driving mutations. However, the presence of many mutations that occur at only low frequency implies that tumours contain multiple subclones, and the relevance of these is not fully understood. On page 113 of this issue, Cleary et al.2 provide a potential explanation for some forms of intratumoral heterogeneity, by describing a
5 2 | NAT U R E | VO L 5 0 8 | 3 A P R I L 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
cooperative cellular interaction in mouse mammary tumours in which the presence of two types of clone is required for tumour formation. Mammary tumours induced by overexpression of the Wnt1 gene are thought to originate in mammary epithelial stem cells3, which can differentiate into both the luminal and basal cells that make up mammary epithelial tissue. These tumour-initiating cells can therefore give rise to tumours composed of cancer cells with either basal or luminal features. It was previously established4 that the coexistence of these two lineages is maintained by paracrine interactions between the two cell types — that is, short-distance interactions mediated by signalling molecules — because only luminal
cells that make up the blood vessels. Hall and co-workers suggest that the longterm reduction of cerebral blood flow after reperfusion of a blocked artery may be at least partly attributable to pericyte rigor mortis — literally ‘the stiffness of death’ (Fig. 1c). In rigor mortis, stiffness results from a lack of ATP molecules, which prevents myosin and actin — two proteins that interact to cause muscle contraction — from being separated from one another. The concept of prolonged vasoconstriction due to strangulation by dead pericytes raises several questions that require further investigation. Why are pericytes, as opposed to other cell types such as endothelial cells, particularly susceptible to ischaemia-induced death? Can pericyte death be prevented, and will this inhibit the no-reflow phenomenon? Is pericyte rigor mortis a factor in this phenomenon after injury in other tissues, particularly in the heart following a heart attack? If this model of ischaemia-induced pericyte rigor mortis remains robust in the face of further analysis, it may pave the way for approaches to combat ischaemic injury that prevent pericyteinduced loss of a tissue’s ability to reperfuse. ■
P L AN ETARY SCIENCE
A chronometer for Earth’s age Simulations of Earth’s growth show a correlation between the timing of the Moon’s formation and the amount of mass that Earth accreted afterwards. This relationship provides a way of measuring the age of our planet. See Letter p.84 JOHN CHAMBERS
T
he age of the oldest objects in the Solar System is known with remarkable precision — 4,567 million years1,2 — thanks to recent strides in the dating of meteorites. Unfortunately, applying the same dating methods to Earth yields an age that is frustratingly fuzzy. Our planet formed sometime during the first 150 million years of the Solar System’s history3–5, but we do not know when. On page 84 of this issue, Jacobson et al.6 propose a way of measuring the time at which Earth finished forming using numerical simulations of the planet’s growth and its chemical composition. Their result: Earth formed in 95 million years, with an uncertainty of about 32–39 million years, making the planet about 4,470 million years old. A big part of the problem with dating Earth is that our planet did not appear overnight. Starting from humble beginnings, Earth gradually accumulated material over an extended
period of time. Indeed, it is still gaining mass today in the form of meteorites and interplanetary dust particles. What is needed is a milestone in Earth’s growth at which we can say that the planet was essentially complete. A widely adopted milestone is the major collision with a planet-sized body that is thought to have formed the Moon7 (Fig. 1). Current theory suggests that Earth experienced several of these ‘giant impacts’ during its formation, with the Moon-forming impact being the last. Each impact mixed together material that would end up in Earth’s metallic core and rocky mantle, as well as adding bulk to both. The prolonged nature of Earth’s growth and the existence of multiple giant impacts complicate the task of dating Earth using radiometric clocks — those that combine known decay rates of radioactive materials with measurements of how these materials and their decay products are distributed within Earth today. For one thing, it is unclear just how much mixing of core and mantle material occurred
Daniel M. Greif and Anne Eichmann are at the Yale Cardiovascular Research Center, Yale University School of Medicine, New Haven, Connecticut 06510, USA. A.E. is also in the Department of Cellular and Molecular Physiology, Yale University School of Medicine, and at the Center for Interdisciplinary Research in Biology, Collège de France, Paris. e-mails: [email protected]; [email protected] 1. Hall, C. N. et al. Nature 508, 55–60 (2014). 2. Rouget, C. Arch. Physiol. Normal Pathol. 5, 603–663 (1873). 3. Daneman, R., Zhou, L., Kebede, A. A. & Barres, B. A. Nature 468, 562–566 (2010). 4. Armulik, A. et al. Nature 468, 557–561 (2010). 5. Bell, R. D. et al. Neuron 68, 409–427 (2010). 6. Bell, R. D. et al. Nature 485, 512–516 (2012). 7. Fernández-Klett, F., Offenhauser, N., Dirnagl, U., Priller, J. & Lindauer, U. Proc. Natl Acad. Sci. USA 107, 22290–22295 (2010). 8. Peppiatt, C. M., Howarth, C., Mobbs, P. & Attwell, D. Nature 443, 700–704 (2006). 9. Cohen, Z., Molinatti, G. & Hamel, E. J. Cereb. Blood Flow Metab. 17, 894–904 (1997). 10. Lindahl, P., Johansson, B. R., Levéen, P. & Betsholtz, C. Science 277, 242–245 (1997). 11. Yemisci, M. et al. Nature Med. 15, 1031–1037 (2009). 12. Vates, G. E., Takano, T., Zlokovic, B. & Nedergaard, M. Nature Med. 16, 959 (2010). This article was published online on 26 March 2014.
with each giant impact, and to what extent the radiometric clocks were reset as a result. Earth probably retains a memory of several of these events, rather than just the last one. Giant impacts may have ejected some of the planet’s more volatile elements into space, distorting radiometric dating systems that assume that all of the radioactive decay products are still present. It is also possible that Earth’s core and mantle continued to interact for some time after the last giant impact. This is where modelling the growth of our planet could pay dividends. The formation of the Sun’s rocky planets probably passed through several stages 8, beginning with micrometre-sized dust grains in the nascent Solar System, proceeding to asteroid-sized bodies known as planetesimals, and then to a few dozen Moon-to-Mars-mass planetary embryos. The accumulation of these planetary embryos into the modern rocky planets through occasional giant impacts was by far the slowest stage, and it largely determined how long Earth took to form. Jacobson et al. have modelled this final growth stage, beginning with various populations of planetary embryos and planetesimals. They also examined two widely different scenarios for what the giant planets of the Solar System were doing during this time. En route, the authors found an interesting and remarkably robust correlation: the timing of the last giant impact on Earth is inversely related to the amount of mass the planet accumulated afterwards from leftover planetesimals. If the last giant impact occurred early on, there would have been plenty of planetesimals left 3 A P R I L 2 0 1 4 | VO L 5 0 8 | NAT U R E | 5 1
© 2014 Macmillan Publishers Limited. All rights reserved
RESEARCH NEWS & VIEWS NASA
planets orbiting very close to their star11. If conditions during the growth of the planets were different from those assumed by Jacobson et al., then the authors’ estimated age for Earth could be incorrect. Despite this caveat, it is encouraging to see studies that combine the fundamental physics inherent in numerical simulations of planet formation with the wealth of information available on Earth’s composition. Understanding how and when the Sun’s planets formed is immensely challenging, and researchers need every tool available. Studies such as the one by Jacobson and colleagues may be the best hope for understanding how and when our planet came to be. ■ John Chambers is in the Department of Terrestrial Magnetism, Carnegie Institution for Science, Washington DC 20015, USA. e-mail: [email protected]
Figure 1 | Earthrise from the Moon. Jacobson et al.6 find that the timing of the Moon-forming impact on Earth is inversely related to the amount of mass that the planet accumulated afterwards.
for Earth to sweep up afterwards. If the last giant impact was late, few planetesimals would have remained, and Earth’s growth would have largely ceased. This correlation provides an independent way of dating the Moon-forming impact, provided that we can measure the amount of material that arrived subsequently. Fortunately, there is a way to do this. Several elements, such as iridium and platinum, show a strong tendency to move into Earth’s core. During the upheaval of each giant impact, these elements leached from the planet’s mantle, bonding with heavy, iron-rich material destined to sink to the core. After the last giant impact, Earth’s mantle should have been almost completely stripped of iridium,platinum and their cousins. In practice, these elements are present in small amounts in the mantle, and in the same relative proportions seen in many meteorites9. To many researchers, this suggests that Earth acquired a fraction of its mass after the last giant impact, when the core and mantle had ceased separating. Jacobson et al. combine the measured mass of this extra material with the correlation from their simulations to date the Moon-forming impact and then deduce Earth’s age. They find it very unlikely that Earth finished forming in the first 38 million years of the Solar System. Their favoured time — 95 million years — is compatible with some radiometric-dating estimates for when Earth’s core finished forming4, and makes Earth comfortably older than the oldest minerals known to have formed in its crust10.
Naturally, Jacobson and colleagues’ method is only as valid as our picture of how planets form. The standard model for planet formation in the Solar System is far from complete, and it has had a torrid time lately trying to explain some aspects of extrasolar planetary systems, such as the existence of Earth-sized
1. Amelin, Y. et al. Earth Planet. Sci. Lett. 300, 343–350 (2010). 2. Connelly, J. N. et al. Science 338, 651–655 (2012). 3. Yin, Q. et al. Nature 418, 949–952 (2002). 4. Allègre, C. J., Manhès, G. & Göpel, C. Earth Planet. Sci. Lett. 267, 386–398 (2008). 5. Halliday, A. N. Phil. Trans. R. Soc. A 366, 4163–4181 (2008). 6. Jacobson, S. A. et al. Nature 508, 84–87 (2014). 7. Canup, R. M. & Asphaug, E. Nature 412, 708–712 (2001). 8. Morbidelli, A., Lunine, J. I., O’Brien, D. P., Raymond, S. N. & Walsh, K. J. Annu. Rev. Earth Planet. Sci. 40, 251–275 (2012). 9. Walker, R. J. Chem. Erde Geochem. 69, 101–125 (2009). 10. Valley, J. W. et al. Nature Geosci. 7, 219–223 (2014). 11. Dong, S. & Zhu, Z. Astrophys. J. 778, 53 (2013).
CA N C ER
Clonal cooperation Widespread genetic heterogeneity in cells of human tumours poses a question: what prevents the fittest clone from taking over? A demonstration of interdependence between distinct clones might shed light on this puzzle. See Letter p.113 K O R N E L I A P O LYA K & A N D R I Y M A R U S Y K
S
equencing of human cancer genomes has revealed a high degree of genetic heterogeneity among cells of a given tumour1. In most cases, tumour growth is thought to be driven by the most ‘advanced’ cancer-cell subpopulation — that carrying the highest number of cancer-driving mutations. However, the presence of many mutations that occur at only low frequency implies that tumours contain multiple subclones, and the relevance of these is not fully understood. On page 113 of this issue, Cleary et al.2 provide a potential explanation for some forms of intratumoral heterogeneity, by describing a
5 2 | NAT U R E | VO L 5 0 8 | 3 A P R I L 2 0 1 4
© 2014 Macmillan Publishers Limited. All rights reserved
cooperative cellular interaction in mouse mammary tumours in which the presence of two types of clone is required for tumour formation. Mammary tumours induced by overexpression of the Wnt1 gene are thought to originate in mammary epithelial stem cells3, which can differentiate into both the luminal and basal cells that make up mammary epithelial tissue. These tumour-initiating cells can therefore give rise to tumours composed of cancer cells with either basal or luminal features. It was previously established4 that the coexistence of these two lineages is maintained by paracrine interactions between the two cell types — that is, short-distance interactions mediated by signalling molecules — because only luminal
