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A Galaxy Cluster Makes Its Mark

Saturday, September 27, 2008

A Galaxy Cluster Makes Its Mark
Abell 1689, shown in this composite image, is a massive cluster of galaxies located about 2.3 billion light years away that shows signs of merging activity. Hundred-million-degree gas detected by NASA's Chandra X-ray Observatory is shown as purple in this image, while galaxies from optical data from the Hubble Space Telescope are colored yellow. The X-ray emission has a smooth appearance, unlike other merging systems such as the Bullet Cluster or MACS J0025.4-1222. The temperature pattern across Abell 1689 is more complicated, however, possibly requiring multiple structures with different temperatures.

The long arcs in the optical image are caused by gravitational lensing of background galaxies by matter in the galaxy cluster, the largest system of such arcs ever found. Further studies of this cluster are needed to explain the lack of agreement between mass estimates based on the X-ray data and on the gravitational lensing. Previous work suggests that filament-like structures of galaxies are located near Abell 1689 along our line-of-sight to this cluster, which may bias mass estimates using gravitational lensing.

Abell 1689 – click for 864×897 image

More: here

mTOR, MAPK, and cancer

Saturday, September 20, 2008

Recent studies are making it increasingly apparent that cancer is really many different diseases – hundreds actually – in the sense that there are hundreds of distinct problems at a molecular level that can result in the symptoms of cancer in a large variety of tissue types. It is necessary to regard all these problems as distinct diseases, because different techniques will be necessary to deal effectively with each one.

One of the things we are now understanding is that it is not simply mutations in a few specific genes that account for most different cancers. Instead, each different type of cancer can be attributed to mutations in one or several genes randomly chosen from a larger set that collectively defines some specific signaling "pathway" in a cell. Or perhaps even several interrelated pathways.

See here for one account of some of the latest research on this. I'd like to discuss the papers that cover this research, but first I'd like to discuss some slightly earlier research that provides a simpler look at the issue.

I've already written about one particular pathway of special importance, the one associated with mTOR. That discussion, from last April, is here.

As you recall, mTOR is a serine/threonine kinase. The pathway in which it plays a prominent part regulates the growth, proliferation, motility, and survival of cells. And also angiogenesis. From that list it should be obvious why malfunctions in the pathway can give rise to cancer. The pathway, in turn, integrates input from a number of upstream pathways, such as those involving intercellular signaling molecules like insulin, IGF-1, and mitogens.

The name mTOR is short for mammalian target of rapamycin. Rapamycin, also known as sirolimus, is a bacterial product that was originally of interest for its antifungal properties. It was subsequently found to have immunosuppressive and antiproliferative properties. These properties, in turn, are a consequence of the fact that rapamycin binds to a protein complex called mTOR complex 1 (mTORC1). The antiproliferative properties, of course, are due to the importance of mTOR in regulating cell proliferation and motility.

All this stuff is well known to cancer biologists and not new. In particular, much research has been devoted to finding useful inhibitors of mTOR. Unfortunately, however, the research hasn't been as successful at actually treating cancer as might have been hoped:

A Role For MAPK Inhibitors Combined With MTORC1 Inhibitors (8/21/08)
Nearly a decade ago, while it was being tested as an immunosuppressive agent to prevent organ rejection in transplant patients, the drug rapamycin was also discovered to have anti-tumor properties. Since then, several rapamycin analogs known as mTOR (mammalian target of rapamycin) inhibitors have been tested in clinical trials for the treatment of various types of cancer.

But despite promising early results, mTOR inhibitors have proven less successful than originally expected.

The problem is that the mTOR inhibitors that have been tried as anti-cancer drugs also seem to stimulate another pathway that promotes cell growth and proliferation:
Now research led by scientists at Beth Israel Deaconess Medical Center (BIDMC) identifies a previously unrecognized problem faced by these agents when it comes to attacking cancers. ... [T]he new findings show that at the same time that rapamycin analogs are halting tumor growth by inhibiting the mTOR protein complex 1 (mTORC1), they are activating the MAPK (mitogen-activated protein kinase) pathway -- thereby encouraging cancer cell survival.

The MAPK pathway has also been under intensive investigation in connection with cancer. As the name implies, kinases in this pathway are activated by mitogens – external signals that promote mitosis. These kinases also affect cell survival and apoptosis. So it's reasonable to guess that adding a MAPK inhibitor to an mTOR inihibitor might counteract the MAPK-stimulating effect of the mTOR inhibitors.

Are you with me? Anyhow, what the new research does is show how there's a feedback loop that connects mTOR inhibition with MAPK activation.

Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer
Numerous studies have established a causal link between aberrant mammalian target of rapamycin (mTOR) activation and tumorigenesis, indicating that mTOR inhibition may have therapeutic potential. In this study, we show that rapamycin and its analogs activate the MAPK pathway in human cancer, in what represents a novel mTORC1-MAPK feedback loop. ... We further show that rapamycin-induced MAPK activation occurs in both normal cells and cancer cells lines and that this feedback loop depends on an S6K-PI3K-Ras pathway.

PI3K is another important signaling kinase about which there is a lot of other interesting current research – which we'll get around to discussing at some point. Ras is a G protein known to be very important in cancer because it activates MAPK pathways.

Are you beginning to get the picture of how complicated cancer can be, due to the interaction of pathways?

Fortunately, the research also shows that MAPK inhibition can offset problems due to mTOR inhibition:
[P]harmacological inhibition of the MAPK pathway enhanced the antitumoral effect of mTORC1 inhibition by rapamycin in cancer cells in vitro and in a xenograft mouse model. Taken together, our findings identify MAPK activation as a consequence of mTORC1 inhibition and underscore the potential of a combined therapeutic approach with mTORC1 and MAPK inhibitors.

Another research group has already confirmed the same thing, using the same MAPK inhibitor (PD0325901):

Anti-tumor Effects Are Enhanced By Inhibiting Two Pathways Rather Than One (8/21/08)
In the second study, Cory Abate-Shen and colleagues, at Columbia University College of Physicians and Surgeons, New York, and the University of Medicine & Dentistry of New Jersey, Piscataway, show that simultaneous inhibition of the mTOR and MAPK signaling pathways inhibited the in vitro growth of prostate cancer cell lines and the in vivo growth of prostate tumors in a mouse model of prostate cancer.

Here's their research paper:

Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model
The AKT/mammalian target of rapamycin (AKT/mTOR) and ERK MAPK signaling pathways have been shown to cooperate in prostate cancer progression and the transition to androgen-independent disease. We have now tested the effects of combinatorial inhibition of these pathways on prostate tumorigenicity by performing preclinical studies using a genetically engineered mouse model of prostate cancer. We report here that combination therapy using rapamycin, an inhibitor of mTOR, and PD0325901, an inhibitor of MAPK kinase 1 (MEK; the kinase directly upstream of ERK), inhibited cell growth in cultured prostate cancer cell lines and tumor growth particularly for androgen-independent prostate tumors in the mouse model.

AKT is yet another family of serine/threonine kinases, often associated with mTOR, that is deeply involved in tumorigenicity. There's a lot of recent research on it that should also be discussed... some other time.

Further reading:

From Metabolism to Oncogenes and Back - Part II – 3/21/08 blog post that discusses many cancer-related signaling pathways, including mTOR, AKT, PI3K, Ras, and their connection with metabolism

Arkaitz Carracedo, Li Ma, Julie Teruya-Feldstein, Federico Rojo, Leonardo Salmena, Andrea Alimonti, Ainara Egia, Atsuo T. Sasaki, George Thomas, Sara C. Kozma, Antonella Papa, Caterina Nardella, Lewis C. Cantley, Jose Baselga, Pier Paolo Pandolfi (2008). Inhibition of mTORC1 leads to MAPK pathway activation through a PI3K-dependent feedback loop in human cancer Journal of Clinical Investigation DOI: 10.1172/JCI34739

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Messier 83 - The "Thousand-Ruby Galaxy"

Thursday, September 11, 2008

The Thousand-Ruby Galaxy (9/2/08)
This dramatic image of the galaxy Messier 83 was captured by the Wide Field Imager at ESO's La Silla Observatory, located high in the dry desert mountains of the Chilean Atacama Desert. Messier 83 lies roughly 15 million light-years away towards the huge southern constellation of Hydra (the sea serpent). It stretches over 40 000 light-years, making it roughly 2.5 times smaller than our own Milky Way. However, in some respects, Messier 83 is quite similar to our own galaxy. Both the Milky Way and Messier 83 possess a bar across their galactic nucleus, the dense spherical conglomeration of stars seen at the centre of the galaxies.

This very detailed image shows the spiral arms of Messier 83 adorned by countless bright flourishes of ruby red light. These are in fact huge clouds of glowing hydrogen gas. Ultraviolet radiation from newly born, massive stars is ionising the gas in these clouds, causing the great regions of hydrogen to glow red. These star forming regions are contrasted dramatically in this image against the ethereal glow of older yellow stars near the galaxy's central hub. The image also shows the delicate tracery of dark and winding dust streams weaving throughout the arms of the galaxy.

Messier 83 – click for 1280×1280 image

The first stars

Monday, September 8, 2008

Once upon a time when the universe was very young, before there were even galaxies that could be "far, far away", the first stars were born.

The story of how this probably happened, which astrophysicists have been trying to figure out for decades, is rather interesting. Only with results announced at the end of July has the story begun to come into good focus.

The main reason is has taken so long to understand how the first stars formed is that it is quite impossible to see individual stars from the earliest era. Indeed, some of the earliest galaxies we can see (consisting of billions of stars), even with our best telescopes, are about 13 billion light-years away, as they looked about 700 million years after the big bang. This corresponds to a redshift of about 7.5. (See here.)

It follows that the first stars had to have formed some time before that, but as of now we have no way to observationally verify an approximate date. Since it takes time for a galaxy to form out of individual stars, the first star probably formed within the first 500 million years or so after the big bang.

The only way, currently, we can even guess when the first star formed is by starting from what we know – the laws of physics and information we have about the composition of the universe in that time period – in order to do computer calculations (simulations) of the process that should have led to formation of the first stars. Results from the best simulation yet performed have recently been announced.

Although we cannot (yet) directly observe conditions or objects existing within the time period in question, we can infer a variety of facts about them. Some of the direct data we have is based on observations of the cosmic microwave background (CMB). This is radiation that is now observed in the microwave part of the spectrum, although it was much more energetic when it originated approximately 380,000 years after the big bang. Additional data came from observations by the Spitzer Space Telescope, announced in 2005, involving diffuse infrared light that began as ultraviolet light emitted by the first stars. (See here.)

What we know of that period is encompassed in what is called the cold dark matter model (CDM) of the universe. Very good evidence from a variety of sources exists for the overall parameters of this model. The parameters include an overall density of matter (both ordinary and dark matter) that is – at the present time – 30% of the total energy density (with the balance being dark energy). Of that 30%, 26% is dark matter and the remaining 4% is ordinary baryonic matter.

These fractions vary with time, because the density of matter is always decreasing as the universe expands. However, since dark energy (in the form of a cosmological constant) is proportional to volume, the amount of dark energy is always increasing, while its density (per unit volume) remains constant. What this means is that in the early universe during the time we're concerned with, the energy density due to matter was a much larger percentage. However, the ratio of dark matter to baryonic matter remained constant, at 6.5 to 1.

In the big bang model, the earliest chemical elements formed, just a few minutes after the big bang, were hydrogen, helium, and a little bit of lithium. (See here.) By mass, about 75% of this matter was hydrogen, and most of the rest was helium. Since these elements are stable, these proportions did not change for hundreds of millions of years – until the first stars formed.

Another thing we know from the CMB is that there were slight variations from place to place in the average density of matter. Over time, the regions which were slightly more dense than average tended to contract under the force of gravity, and these regions continued to grow denser, relative to everything else.

Eventually there were distinct, though rather diffuse, clouds consisting of dark matter, hydrogen atoms, hydrogen molecules (H2), and a little helium. The rate of collapse at this point is very much driven by the dark matter, since there's 6 times as much of it as of ordinary matter. In these low-density clouds, the pressure due to kinetic energy of gas particles was low compared to the force of gravitation.

You may be wondering why star formation at this early time is such a mystery. After all, stars are forming all the time in the present day. The process is more complex than might at first be supposed, but we have reasonable, albeit incomplete, models of how it happens, and there isn't any great mystery. We can, for example, predict that unless a gas cloud is sufficiently massive, it won't collapse to form a star at all. That is, the gas cloud will never become hot enough and dense enough for thermonuclear reactions to start, so that there is a sustainable source of energy (other than gravitational) to enable the star to shine. Instead, what you get from a cloud that's too small is a brown dwarf, essentially just a ball of gas where there is equilibrium between gravitational force and gas pressure.

But what stellar models show is that even if you start with a sufficiently large cloud of gas, in order that it can collapse far enough to begin thermonuclear reactions it is necessary, paradoxically, that at some point along the way the cloud can dispose of some of its internal kinetic energy. Unless this happens, the cloud has too much internal energy, so its pressure is too high, and equilibrium is reached before the cloud is dense enough to go thermonuclear.

The models further show that the factor which allows energy to be radiated away at the right time is the presence of enough heavy elements. But the kicker is that there were no heavy elements in the early universe – only hydrogen and helium. All other elements up to iron in atomic weight were formed in the first stars from internal thermonuclear reactions. And these elements were only distributed into the interstellar medium when stars of the first generation that were sufficiently large exploded as supernovae, and in the process created all other, heavier chemical elements as well.

But what hasn't been clear, until now, is whether stars could form at all without elements heavier than helium. Perhaps the most that could happen, unless individual clouds were extremely massive, is that contraction would stall, as it does in brown dwarfs. On the other hand, if a gas cloud is too massive, it might be unstable and explode before entering a star-like state that is stable for some significant length of time. In the present universe, the largest known stars have masses around 100 times the mass of our sun, and such stars live only a million years or so before going supernova.

Fortunately, the new simulations now show how stars could form from sufficiently large clouds, even in the absence of heavy elements.

The set of simulations reported on here starts with conditions as they were about 300 million years after the big bang (corresponding to a redshift of 14). One example starts with a gravitationally bound gas cloud of 500,000 solar masses (M), mostly dark matter. This cloud had a temperature of 1000 K, hydrogen and helium atoms, and a small fraction of molecular hydrogen, which enabled efficient radiative cooling to begin with.

The simulation proceeded through a range of 20 orders of magnitude in density, covering about 100,000 years. In the process, the gas became mostly opaque to radiation, so radiative cooling ceased. This means that from then on, the process was "adiabatic", unable to dissipate internal kinetic energy, so that temperature rose quickly. At a certain point in the simulation, a flattened disk-like structure of .1 M formed. Because the disk was thin, radiation could escape in a perpendicular direction, allowing further cooling. The final outcome, after several other stages, was a .01 M protostar – defined as a pressure-supported, constant-density atomic gas core.

The temperature of this protostar was 10,000 K, far short of what is needed for thermonuclear reactions. And the protostar was not especially dense – about the same as ordinary water. At this point, however, the simulation exhibited strong shock waves in the hot gas. The simulation stopped here because of the complexity of the protostar. So there is definitely further work to be done. The simulation did not reach the point where thermonuclear reactions would start, but it's a big step anyway, roughly halfway to the final goal.

At the point where the simulation ended, gas was accreting from the surrounding cloud rapidly enough to allow growth to 10 M in just 1000 years. This could continue to 100 M or more, which is the expected size of the largest initial stars. However, growth might stop short of that figure, if radiation pressure from thermonuclear reactions rises too fast. On the other hand, if the star grows to much more than 100 M, it could collapse into a black hole, taking the heavy elements with it. Only further simulations can clarify what might happen.

Several lines of evidence show that extremely massive (~100 M) stars existed in the first generation. For instance, there were stars large enough and hot enough to emit photons with enough energy to ionize hydrogen atoms. We know that before stars existed, all hydrogen must have been in the form of an unionized gas – yet before a billion years after the big bang, most of the hydrogen was ionized again. In addition, studies of the CMB indicate a large contribution of light from very bright stars and galaxies in that early time.

There are several other important results from these simulations. One is that it is actually much easier to simulate in detail the formation of the earliest stars than of later generations. This is because in the present universe there are a number of complicating factors, such as relatively abundant heavy elements, strong magnetic fields, and significant turbulence, that raise large obstacles to simulation. Being able to simulate star formation under simpler conditions is an important step to making good simulations under present conditions.

Another valuable result of full simulation of the earliest stars is the ability to predict what galaxies composed of such stars will look like (in terms of color, size, and luminosity) when we are eventually able to detect them with the upcoming James Webb Space Telescope after its projected launch in 2013. Having the predictions available beforehand will help increase confidence in the validity of the whole model.

Further reading:

Protostar Formation in the Early Universe – research article published 8/1/08 in Science

The Cosmic Rosetta Stone – commentary on the research, published 8/1/08 in Science

New simulation accurately tracks seeds of first stars – 7/31/08 news article in Science News

Filling the Gap in Stellar History – 7/31/08 news article in ScienceNOW

Universe's first stars bulk up in new simulation – 7/31/08 New Scientist news article

The first stars – 7/31/08 press release

Additional news reports:

N. Yoshida, K. Omukai, L. Hernquist (2008). Protostar Formation in the Early Universe Science, 321 (5889), 669-671 DOI: 10.1126/science.1160259


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