NEWS & VIEWS RESEARCH transition from the motile to the sessile state and the switch in the other direction. The shift from the motile to the sessile state seems to be completely random and independent of how long the bacterium has been in the motile state. This motile state, therefore, is ‘memoryless’. The switch from the sessile to the motile state, however, is not random and is tightly timed: cells remain in the sessile state for roughly eight generations. The authors suggest that this memory serves a cellular function, ensuring that switching to the motile state, which breaks the chain almost immediately, does not occur too soon or with too much delay, which could result in some chains overflowing with millions of cells. The transition to the sessile state probably represents a trial period of multicellularity, which could be reinforced by environmental signals to commit the cells to forming a biofilm. Norman and co-workers also explore the molecular mechanism that controls the cellfate switch. It seems to involve a simple circuit consisting of only three proteins3 (Fig. 1). Specifically, the protein SinR represses the gene encoding another protein, SlrR; in turn, SlrR binds to and titrates SinR. Thus, these two proteins form a double-negative feedback switch. When SinR wins, the cell enters a motile state; when SinR loses, the cell becomes sessile. The third protein, SinI, affects which outcome wins by binding to, and inactivating, SinR. The circuit seems to be modular, as the authors find that SinI is responsible for the memoryless entry into the sessile state. Once the bacteria are in the sessile state, however, SinI is no longer relevant, and the memory is set by the SlrR–SinR feedback loop. Such modularity has also been observed in another B. subtilis circuit that controls a developmental switch. Under stress conditions, B. subtilis can transiently enter a competent state, allowing it to take up external DNA4. The core circuitry that controls entry into the competent state has only a few components, similar to the SlrR– SinR–SinI network. The competence circuit is modular because one component regulates the frequency of transitions into the competent state, whereas another component determines how long a cell remains in this state4. It is unclear what advantage, if any, such modularity has for the cell. Can having independent control of the initiation and duration of differentiation events enable the cell to adapt to independent selective pressures during evolution? And it remains to be seen whether such modularity is a general feature of circuits that control cell-identity switching. The authors also raise questions about how the SlrR–SinR–SinI circuit controls cell-fate switching in B. subtilis. How noise, or variability, in one of the circuit components drives initiation into a sessile state remains unclear. Although initiation requires SinI, it is not known which circuit component exhibits random fluctuations to drive the random switch
into the sessile state, or how these fluctuations are generated. It would be interesting to test the hypothesis that memory in state switching allows a trial window of multicellularity that is reinforced by environmental signals. One approach could be to examine what effect extending or reducing the memory of the sessile state has on biofilm formation. Norman and colleagues’ SlrR–SinR–SinI circuit joins a growing list of bacterial simple genetic circuits that have been shown to control surprisingly complex cellular dynamics. Such circuits often consist of only three or four proteins but can generate pulses5, excitable dynamics4 and robust oscillations6. Might simple genetic circuits generate a similar wealth of regulatory dynamics in plants and animals? Results in cows suggest7 that the concept of memory in state switching could be quite general. Research honoured with the 2013 Ig Nobel prize in probability showed that,
in cows, the standing (motile) state is memoryless, whereas the lying down (sessile) state is timed, just as in B. subtilis. ■ James C. W. Locke is in the Sainsbury Laboratory, University of Cambridge, Cambridge CB2 1LR, UK. e-mail: [email protected] 1. Norman, T. M., Lord, N. D., Paulsson, J. & Losick, R. Nature 503, 481–486 (2013). 2. Wang, P. et al. Curr. Biol. 20, 1099–1103 (2010). 3. Chai, Y., Norman, T., Kolter, R. & Losick, R. Genes Dev. 24, 754–765 (2010). 4. Süel, G. M., Kulkarni, R. P., Dworkin, J., Garcia-Ojalvo, J. & Elowitz, M. B. Science 315, 1716–1719 (2007). 5. Locke, J. C. W., Young, J. W., Fontes, M., Hernández Jiménez, M. J. & Elowitz, M. B. Science 334, 366–369 (2011). 6. Mackey, S. R., Golden, S. S. & Ditty, J. L. Adv. Genet. 74, 13–53 (2011). 7. Tolkamp, B. J., Haskell, M. J., Langford, F. M., Roberts, D. J. & Morgan, C. A. Appl. Anim. Behav. Sci. 124, 1–10 (2010). This article was published online on 20 November 2013.
ASTR O PH YS I CS
Exception tests the rules Detailed observations of an intermittent ultraluminous X-ray source indicate that its emission is unlikely to be powered by mass accretion onto an intermediate-mass black hole as previously thought. See Letter p.500 K. D. KUNTZ
U
ltraluminous X-ray sources (ULXs) are extragalactic sources of X-rays, powered by black holes, that are not coincident with galactic nuclei and have luminosities greater than 1039 erg per second — roughly the highest luminosity that stellar-mass black holes, which weigh less than about 30 solar masses, should be able to achieve. Many types of X-ray source could fit this definition, and there has been a recent multiplication of ULX types. On page 500 of this issue, Liu et al.1 use an intermittent ULX in the spiral galaxy M 101 — an object that purists might argue is not a ‘real’ ULX — to show that several aspects of our understanding of ULXs and, indeed, of black-hole formation, may need to be revised. The luminosity and spectrum of this object, known as M 101 ULX-1 (Fig. 1), had suggested that it is an intermediate-mass black hole2. These black holes have masses in the range of 100 to 1,000 solar masses, and so are larger than black holes formed by the collapse of single massive stars, but smaller than the supermassive black holes that lurk in galactic nuclei. However, Liu and colleagues’ radial-velocity measurements of M 101 ULX-1 show that it
is likely to be a black hole with a mass of only 20–30 solar masses. It is not an intermediatemass black hole, even though commonly used relations between mass, luminosity and temperature imply that it should be. The Eddington luminosity of an accreting black hole occurs when the pressure of the infalling material that will produce radiation is balanced by the outward radiation pressure. This simple physical argument sets the maximum luminosity for a given black-hole mass, or the minimum mass an accretor must have to produce a given luminosity. High luminosities require high fuelling (accretion) rates, which require the black hole to have a stellar companion to provide the fuel. This, in turn, requires the black hole to have formed from the collapse of a massive star, and to have a mass less than about 30 solar masses. A typical ULX, at the Eddington luminosity, must have a minimum mass of 100 to 1,000 solar masses, much larger than predicted by our understanding of how stars become black holes. Thus, either our knowledge of the stellar evolution leading to black holes is wrong, or our simple picture of accretion is wrong. Indeed, mechanisms for accretion beyond the Eddington limit have been proposed 3, although their likelihood remains unclear.
2 8 NOV E M B E R 2 0 1 3 | VO L 5 0 3 | NAT U R E | 4 7 7
© 2013 Macmillan Publishers Limited. All rights reserved
Most of the time, M 101 ULX-1 the accretion disk. But the authors has a luminosity 100-fold less now confirm a previous suggesthan that of the ULX definition, tion6 that it is a Wolf–Rayet star, an but it occasionally flares into evolved massive star undergoing the ULX regime. Liu et al. show strong mass loss. The spectrothat the mass of M 101 ULX-1 is scopic observations also suggest probably 20–30 solar masses, so that the system does not have the its luminosity in outburst greatly low metallicity (abundance of eleexceeds the Eddington limit. But ments other than hydrogen and because the outbursts are relahelium) that has come to be assotively short (less than a week), this ciated with ULXs7. ULX-1 super-Eddington luminosity may Thus, although these properties be understandable. Thus, one mean that M 101 ULX-1 is not a might not think this source inter‘classic’ ULX, it was formerly a esting. However, M 101 ULX-1 particularly good intermediatecontradicts another common mass black-hole candidate. It is understanding about ULXs. systems such as these that, when Under some highly simplifying studied in this detail, will allow assumptions, standard-accretion us to determine the conditions models predict the mass of a black under which super-Eddington hole to be proportional to T −4, accretion occurs, whether ULX where T, which is determined luminosities are super-Eddington, through spectral fitting4, is the and whether intermediate-mass characteristic temperature of a Figure 1 | The host galaxy of ultraluminous X-ray source M 101 ULX-1. black holes are really needed to disk formed from the infalling The source is very faint in this image. explain ULXs. ■ material. More-massive accretors have lower disk temperatures. The disk may, in fact, be stellar-mass systems. K. D. Kuntz is in the Henry A. Rowland temperatures of ULXs are lower than those Liu and colleagues remind us of the need Department of Physics and Astronomy, of Galactic black-hole binary systems with for multi-wavelength data to understand these Johns Hopkins University, Baltimore, measured masses, but at a given disk tem- objects; they used data from a deep year-long Maryland 21218, USA. perature, ULXs have luminosities that are monitoring campaign with the Chandra X-ray e-mail: [email protected] 100-fold higher5. This difference has been Observatory, extensive optical imaging by the taken as tentative evidence that ULXs are Hubble Space Telescope, and a major spectro- 1. Liu, J.-F., Bregman, J. N., Bai, Y., Justham, S. & Crowther, P. Nature 503, 500–503 (2013). indeed much more massive than stellar-mass scopic programme with the 8.1-metre Gemini 2. Kong, A., Di Stefano, R. & Yuan, F. Astrophys. J. 617, black holes. However, Liu et al. use archival telescope, although some of these data were L49–L52 (2004). X-ray data to show that M 101 ULX-1, in obtained for other reasons. They have managed 3. Begelman, M. Astrophys. J. 551, 897–906 (2001). outburst, has the low temperature expected to resolve the controversial issue of the nature 4. Makishima, K. et al. Astrophys. J. 535, 632–643 (2000). from a ULX, despite being a stellar-mass black of the optical counterpart to M 101 ULX-1. 5. Miller, J. M., Fabian, A. C. & Miller, M. C. Astrophys. J. hole. Thus, other ULXs previously thought This was once thought to be a massive ‘B super 614, L117–L120 (2004). to be intermediate-mass black holes on the giant star’, and then a lower-mass ‘F star’ whose 6. Liu, J. F. Astrophys. J. 704, 1628–1639 (2009). basis of their luminosity and temperature emission was drowned in the optical light from 7. Prestwich, A. et al. Astrophys. J. 769, 92 (2013). MOLECUL AR B IO LO GY
Antibiotic re-frames decoding Ketolide antibiotics have been found to induce a ribosomal frameshift — a change in the way that RNA is translated — in bacteria. This promotes the expression of a gene for antibiotic resistance, and may have broader implications. J O H N F. AT K I N S & PAV E L V. B A R A N O V
M
essenger RNAs encode proteins using a sequence of codons: triplets of nucleotides that specify different amino acids. But for a codon sequence to be interpreted, the right reading frame must be set at the start of decoding — translation must begin at the first nucleotide of a codon, rather
than at the second or third. Switching from the correct frame to one of the two alternatives occurs rarely, except at specific places within coding sequences where such frameshifting is programmed. Writing in Molecular Cell, Gupta et al.1 report the exciting finding that antibiotics known as ketolides induce frameshifting. This happens during the expression of one of the short coding sequences that often precede
4 7 8 | NAT U R E | VO L 5 0 3 | 2 8 NOV E M B E R 2 0 1 3
© 2013 Macmillan Publishers Limited. All rights reserved
and regulate the expression of genes that encode functional proteins, and is a previously unknown means for such regulation. Many antibiotics target the ribosome, the nanometre-scale machine in which genetic information is decoded from RNA and translated into proteins in all known living organisms. Certain genes provide bacteria with resistance mechanisms against these antibiotics, such as by encoding proteins that modify ribosomes to prevent antibiotics from binding. But how do these genes sense antibiotics and trigger the synthesis of such defence proteins? Macrolide antibiotics are sensed in bacteria by their effect on ribosomes that are synthesizing the protein product of a ‘leader’ sequence. From the perspective of the direction of ribosome movement, the leader RNA lies upstream of the sequence encoding the defence protein. The defence protein is not synthesized in the absence of antibiotics, because its translational start site is hidden in a region of the mRNA that folds in on itself to form a hairpin-like
JIFENG LIU/SDSS
RESEARCH NEWS & VIEWS
into the sessile state, or how these fluctuations are generated. It would be interesting to test the hypothesis that memory in state switching allows a trial window of multicellularity that is reinforced by environmental signals. One approach could be to examine what effect extending or reducing the memory of the sessile state has on biofilm formation. Norman and colleagues’ SlrR–SinR–SinI circuit joins a growing list of bacterial simple genetic circuits that have been shown to control surprisingly complex cellular dynamics. Such circuits often consist of only three or four proteins but can generate pulses5, excitable dynamics4 and robust oscillations6. Might simple genetic circuits generate a similar wealth of regulatory dynamics in plants and animals? Results in cows suggest7 that the concept of memory in state switching could be quite general. Research honoured with the 2013 Ig Nobel prize in probability showed that,
in cows, the standing (motile) state is memoryless, whereas the lying down (sessile) state is timed, just as in B. subtilis. ■ James C. W. Locke is in the Sainsbury Laboratory, University of Cambridge, Cambridge CB2 1LR, UK. e-mail: [email protected] 1. Norman, T. M., Lord, N. D., Paulsson, J. & Losick, R. Nature 503, 481–486 (2013). 2. Wang, P. et al. Curr. Biol. 20, 1099–1103 (2010). 3. Chai, Y., Norman, T., Kolter, R. & Losick, R. Genes Dev. 24, 754–765 (2010). 4. Süel, G. M., Kulkarni, R. P., Dworkin, J., Garcia-Ojalvo, J. & Elowitz, M. B. Science 315, 1716–1719 (2007). 5. Locke, J. C. W., Young, J. W., Fontes, M., Hernández Jiménez, M. J. & Elowitz, M. B. Science 334, 366–369 (2011). 6. Mackey, S. R., Golden, S. S. & Ditty, J. L. Adv. Genet. 74, 13–53 (2011). 7. Tolkamp, B. J., Haskell, M. J., Langford, F. M., Roberts, D. J. & Morgan, C. A. Appl. Anim. Behav. Sci. 124, 1–10 (2010). This article was published online on 20 November 2013.
ASTR O PH YS I CS
Exception tests the rules Detailed observations of an intermittent ultraluminous X-ray source indicate that its emission is unlikely to be powered by mass accretion onto an intermediate-mass black hole as previously thought. See Letter p.500 K. D. KUNTZ
U
ltraluminous X-ray sources (ULXs) are extragalactic sources of X-rays, powered by black holes, that are not coincident with galactic nuclei and have luminosities greater than 1039 erg per second — roughly the highest luminosity that stellar-mass black holes, which weigh less than about 30 solar masses, should be able to achieve. Many types of X-ray source could fit this definition, and there has been a recent multiplication of ULX types. On page 500 of this issue, Liu et al.1 use an intermittent ULX in the spiral galaxy M 101 — an object that purists might argue is not a ‘real’ ULX — to show that several aspects of our understanding of ULXs and, indeed, of black-hole formation, may need to be revised. The luminosity and spectrum of this object, known as M 101 ULX-1 (Fig. 1), had suggested that it is an intermediate-mass black hole2. These black holes have masses in the range of 100 to 1,000 solar masses, and so are larger than black holes formed by the collapse of single massive stars, but smaller than the supermassive black holes that lurk in galactic nuclei. However, Liu and colleagues’ radial-velocity measurements of M 101 ULX-1 show that it
is likely to be a black hole with a mass of only 20–30 solar masses. It is not an intermediatemass black hole, even though commonly used relations between mass, luminosity and temperature imply that it should be. The Eddington luminosity of an accreting black hole occurs when the pressure of the infalling material that will produce radiation is balanced by the outward radiation pressure. This simple physical argument sets the maximum luminosity for a given black-hole mass, or the minimum mass an accretor must have to produce a given luminosity. High luminosities require high fuelling (accretion) rates, which require the black hole to have a stellar companion to provide the fuel. This, in turn, requires the black hole to have formed from the collapse of a massive star, and to have a mass less than about 30 solar masses. A typical ULX, at the Eddington luminosity, must have a minimum mass of 100 to 1,000 solar masses, much larger than predicted by our understanding of how stars become black holes. Thus, either our knowledge of the stellar evolution leading to black holes is wrong, or our simple picture of accretion is wrong. Indeed, mechanisms for accretion beyond the Eddington limit have been proposed 3, although their likelihood remains unclear.
2 8 NOV E M B E R 2 0 1 3 | VO L 5 0 3 | NAT U R E | 4 7 7
© 2013 Macmillan Publishers Limited. All rights reserved
Most of the time, M 101 ULX-1 the accretion disk. But the authors has a luminosity 100-fold less now confirm a previous suggesthan that of the ULX definition, tion6 that it is a Wolf–Rayet star, an but it occasionally flares into evolved massive star undergoing the ULX regime. Liu et al. show strong mass loss. The spectrothat the mass of M 101 ULX-1 is scopic observations also suggest probably 20–30 solar masses, so that the system does not have the its luminosity in outburst greatly low metallicity (abundance of eleexceeds the Eddington limit. But ments other than hydrogen and because the outbursts are relahelium) that has come to be assotively short (less than a week), this ciated with ULXs7. ULX-1 super-Eddington luminosity may Thus, although these properties be understandable. Thus, one mean that M 101 ULX-1 is not a might not think this source inter‘classic’ ULX, it was formerly a esting. However, M 101 ULX-1 particularly good intermediatecontradicts another common mass black-hole candidate. It is understanding about ULXs. systems such as these that, when Under some highly simplifying studied in this detail, will allow assumptions, standard-accretion us to determine the conditions models predict the mass of a black under which super-Eddington hole to be proportional to T −4, accretion occurs, whether ULX where T, which is determined luminosities are super-Eddington, through spectral fitting4, is the and whether intermediate-mass characteristic temperature of a Figure 1 | The host galaxy of ultraluminous X-ray source M 101 ULX-1. black holes are really needed to disk formed from the infalling The source is very faint in this image. explain ULXs. ■ material. More-massive accretors have lower disk temperatures. The disk may, in fact, be stellar-mass systems. K. D. Kuntz is in the Henry A. Rowland temperatures of ULXs are lower than those Liu and colleagues remind us of the need Department of Physics and Astronomy, of Galactic black-hole binary systems with for multi-wavelength data to understand these Johns Hopkins University, Baltimore, measured masses, but at a given disk tem- objects; they used data from a deep year-long Maryland 21218, USA. perature, ULXs have luminosities that are monitoring campaign with the Chandra X-ray e-mail: [email protected] 100-fold higher5. This difference has been Observatory, extensive optical imaging by the taken as tentative evidence that ULXs are Hubble Space Telescope, and a major spectro- 1. Liu, J.-F., Bregman, J. N., Bai, Y., Justham, S. & Crowther, P. Nature 503, 500–503 (2013). indeed much more massive than stellar-mass scopic programme with the 8.1-metre Gemini 2. Kong, A., Di Stefano, R. & Yuan, F. Astrophys. J. 617, black holes. However, Liu et al. use archival telescope, although some of these data were L49–L52 (2004). X-ray data to show that M 101 ULX-1, in obtained for other reasons. They have managed 3. Begelman, M. Astrophys. J. 551, 897–906 (2001). outburst, has the low temperature expected to resolve the controversial issue of the nature 4. Makishima, K. et al. Astrophys. J. 535, 632–643 (2000). from a ULX, despite being a stellar-mass black of the optical counterpart to M 101 ULX-1. 5. Miller, J. M., Fabian, A. C. & Miller, M. C. Astrophys. J. hole. Thus, other ULXs previously thought This was once thought to be a massive ‘B super 614, L117–L120 (2004). to be intermediate-mass black holes on the giant star’, and then a lower-mass ‘F star’ whose 6. Liu, J. F. Astrophys. J. 704, 1628–1639 (2009). basis of their luminosity and temperature emission was drowned in the optical light from 7. Prestwich, A. et al. Astrophys. J. 769, 92 (2013). MOLECUL AR B IO LO GY
Antibiotic re-frames decoding Ketolide antibiotics have been found to induce a ribosomal frameshift — a change in the way that RNA is translated — in bacteria. This promotes the expression of a gene for antibiotic resistance, and may have broader implications. J O H N F. AT K I N S & PAV E L V. B A R A N O V
M
essenger RNAs encode proteins using a sequence of codons: triplets of nucleotides that specify different amino acids. But for a codon sequence to be interpreted, the right reading frame must be set at the start of decoding — translation must begin at the first nucleotide of a codon, rather
than at the second or third. Switching from the correct frame to one of the two alternatives occurs rarely, except at specific places within coding sequences where such frameshifting is programmed. Writing in Molecular Cell, Gupta et al.1 report the exciting finding that antibiotics known as ketolides induce frameshifting. This happens during the expression of one of the short coding sequences that often precede
4 7 8 | NAT U R E | VO L 5 0 3 | 2 8 NOV E M B E R 2 0 1 3
© 2013 Macmillan Publishers Limited. All rights reserved
and regulate the expression of genes that encode functional proteins, and is a previously unknown means for such regulation. Many antibiotics target the ribosome, the nanometre-scale machine in which genetic information is decoded from RNA and translated into proteins in all known living organisms. Certain genes provide bacteria with resistance mechanisms against these antibiotics, such as by encoding proteins that modify ribosomes to prevent antibiotics from binding. But how do these genes sense antibiotics and trigger the synthesis of such defence proteins? Macrolide antibiotics are sensed in bacteria by their effect on ribosomes that are synthesizing the protein product of a ‘leader’ sequence. From the perspective of the direction of ribosome movement, the leader RNA lies upstream of the sequence encoding the defence protein. The defence protein is not synthesized in the absence of antibiotics, because its translational start site is hidden in a region of the mRNA that folds in on itself to form a hairpin-like
JIFENG LIU/SDSS
RESEARCH NEWS & VIEWS
