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Human cytomegalovirus and glioblastoma

Saturday, May 31, 2008

The timing of news about these related topics is interesting.

Common Virus May Serve As Target For Vaccine In Fight Against Deadly Brain Tumors (5/16/08)
A type of herpes virus called human cytomegalovirus (CMV) is found in up to 80 percent of Americans, though the virus normally produces very few clinical symptoms, is dormant, and usually undetectable in most people. However, more than 80 percent of patients newly diagnosed with the brain cancer glioblastoma multiforme (GBM) exhibit detectable CMV in their blood as well as in their tumors. The Duke team thought this might provide an opportunity to target brain tumors by going after the virus.

"Previous work has demonstrated the activation of this virus in patients with GBMs, so we took it one step further and tested a vaccine, in a small group of patients, that seems to show some efficacy in stalling the recurrence of these deadly tumors," said Duane Mitchell, M.D., Ph.D., a Duke researcher and lead investigator on the study. "We knew there was a connection between this virus and the brain cancer, and we were hoping to take advantage of that connection to treat one by treating the other."

The fact that glioblastoma multiforme and human cytomegalovirus occur together doesn't automatically mean that the latter "causes" the former, in the way that human papilloma virus (HPV) is known to cause cervical caner. Indeed, the fact that CMV is endemic, while GBM isn't, means that the story has to be more complicated. (The Wikipedia article even cites research (from 2003) that did not find a link between GBM and viral infection.)

However, the fact that a vaccine based on CMV seems to have some effect on GBM, means the relationship has to be more than fortuitous:
There were 21 patients enrolled in the trial, and the vaccine appears to have delayed the re-growth of tumors from a typical six to seven months after surgery to more than 12 months. Early results also show a lengthened overall survival among GBM patients, from about 14 months with standard treatment to greater than 20 months.

This still doesn't prove that CMV "causes" GBM. For instance, the tumor environment of GBM may simply be more supportive of the virus. But just having CMV more prevalent in GBM tumors makes it possible for a vaccine to work, because the vaccine causes the immune system to target cells that contain CMV.

Here's some other recent research that addresses the relationship. In fact, it shows just how CMV is tumorigenic.

Virus Mimics Human Protein To Hijack Cell Division Machinery (5/8/08)
Viruses are masters of deception, duping their host's cells into helping them grow and spread. A new study has found that human cytomegalovirus (HCMV) can mimic a common regulatory protein to hijack normal cell growth machinery, disrupting a cell's primary anti-cancer mechanism.

Writing in the May 9 issue of Science, researchers from the University of Wisconsin-Madison and Harvard Medical School report that a viral protein, called UL97, masquerades as a normal regulatory enzyme to modify a tumor-suppressing protein in human cells. Unlike the normal enzyme, which can be switched on and off by the cell as needed, the viral stand-in lacks an off switch and evades cellular control. The findings represent a previously unknown way that viruses can cause uncontrolled cell growth and division.

But this still doesn't address the question of why, if CMV is in 50% to 80% of the population, GBM is so rare. Or, indeed, why GBM is the only sort of cancer with which CMV seems to be associated. Whatever the relaltionship really is, it's apparently somewhat tenuous.

Update 6/4/08:

Here's another news report on the vaccine that just appeared. There will probably be more, since the results sound pretty encouraging.

Vaccine doubles brain cancer survival time
A vaccine that more than doubles the survival time of patients with the most common and aggressive form of brain cancer has been developed by scientists.

Early results from clinical trials suggest patients who received the vaccine lived for nearly three years after being diagnosed with glioblastoma multiforme.

Update, 7/16/08: More recent news story: Does Herpes Cause Brain Cancer? (7/3/08)

Further reading:

Phosphorylation of Retinoblastoma Protein by Viral Protein with Cyclin-Dependent Kinase Function – Research article in 5/9/08 Science about tumorigenicity of CMV

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And this is infotainment too

Thursday, May 29, 2008

Yahoo CEO says company is not 'under siege'
Yang and Yahoo President Susan Decker said the company was reorganizing around four pillars: home page, search, mail and mobile services.

"The essence of Yahoo is being defined today," Yang said. "We have to be incredibly relevant to the consumer. We want you to start your day at Yahoo."

Now I get it. Just an online version of "Good Morning America" (a property of the Mickey Mouse company). (Prediction: Yahoo! will be acquired by Disney. It's a much better fit than with Microsoft. (Regarding which, see here.) And if it happens, you read it here first.)

And exactly when will people wake up to realize they are being insulted when referred to as "consumers"?

This is infotainment

Japanese scientists create microscopic noodle bowl
Japanese scientists say they have used cutting-edge technology to create a noodle bowl so small it can be seen only through a microscope.

Mechanical engineering professor Masayuki Nakao said Thursday he and his students at the University of Tokyo used a carbon-based material to produce a noodle bowl with a diameter 1/25,000 of an inch in a project aimed at developing nanotube-processing technology.

A "carbon-based material"? Aren't all of us carbon-based materials?

What on Earth does the writer of this piece think the information level of readers has sunk to, if it's necessary to use such a locution instead of "carbon nanotube"? And since when is "1/25,000 of an inch" a better way to say "1 micron"?
The Japanese-style ramen bowl was carved out of microscopic nanotubes, Nakao said.

Nanotubes are tube-shaped pieces of carbon, measuring about one-ten-thousandth of the thickness of a human hair.

Carbon nanotubes are being explored for a wide range of uses in electronics and medicine because their structure endows them with powerful physical properties such as a strength greater than steel.

What's The Difference Between A Human And A Fruit Fly?

Tuesday, May 27, 2008

Not a whole lot, by objective standards. Wait... is this a trick question? Maybe. Turns out you can tell the difference by looking at protein interactions. (Technically, this is part of the "interactome".)

What's The Difference Between A Human And A Fruit Fly?
Fruit flies are dramatically different from humans not in their number of genes, but in the number of protein interactions in their bodies, according to scientists who have developed a new way of estimating the total number of interactions between proteins in any organism.

The new research, published May 13, 2008 in the Proceedings of the National Academy of Sciences journal, shows that humans have approximately 10 times more protein interactions than the simple fruit fly, and 20 times as many as simple, single-cell yeast organisms.

This contradicts comparisons between the numbers of genes in different organisms, which yield surprising results: humans have approximately 24,000 genes, but fruit flies are not far behind, with approximately 14,000 genes.

Surprisingly little seems to be known about how many actual genes different organisms have. It's relatively easy to figure out the size of an organism's complete genome, which is the number of base pairs in its DNA. (In just a single copy of the total genome, that is. Humans have 2 sets of chromosomes, hence two copies. But one bacterial species, Epulopiscium, has tens of thousands of copies of its genome. See here.)

You can find a table of a few different genome sizes here, and for more on genome size see here. Anyhow, this number varies dramatically. Humans have about 3.2 billion base pairs, but there's an amoeba, Amoeba dubia that has 670 billion base pairs, the largest size genome known. For a little more on genome size, see here.

Determining the actual number of genes is quite a bit harder, as some genomes contain a great deal of DNA that is not part of any gene. (This used to be called "junk DNA", but it's now realized that much of this DNA is actually important. We just don't know exactly what it's important for.) As we discussed here, it has finally been determined, after quite a bit of study, that there are about 20,500 human genes. (So the number 24,000 quoted above is an earlier, less exact estimate.)

For genomes which have not been studied as intensively as those of humans and fruit flies, our estimates on the number of genes are less certain. But, for example, corn has about 50,000 genes. So what is interesting is that most relatively complex organisms have numbers of genes numbering in the low tens of thousands.

An interesting question, then, based on the research cited at the beginning of this note, is why evolution has chosen to implement complexity through increasing the number of protein interactions rather than the number of actual genes.

At present, this question can only be speculated on. But it seems that some simple considerations of probabilities would lead us to have predicted the outcome.

Apparently, nature finds it relatively difficult to create new genes. New genes are created when a genome acquires two or more copies of an existing gene. Usually additional copies come about (over multiple generations) when it is useful to an organism to produce larger amounts of a certain protein, since two copies of a gene would be expected to result in about twice as much of its corresponding protein.

But as soon as there are multiple copies of any gene, the copies can start to diverge from each other in their exact sequence, if the protein they originally code for becomes less critical. The result is two or more genes that gradually, over many generations, code for slightly different proteins, which may come to have very different functions.

However, what we apparently have to conclude from the fruit fly research, is that changes to an organism's phenotype (roughly, its physical form) are rather more likely to occur when genetic changes are so slight that they don't lead to actual new genes, but instead merely large enough to alter a protein only enough to change how it interacts with some, probably just a few, other proteins.

We still don't know how many distinct proteins are actually produced, even in humans. We do know the number is much larger than the number of different genes, because of alternative splicing. In humans, this number might be in the hundreds of thousands. Whatever the actual number (call it N) is, the number of possible interactions within the set is astronomical, since the number of distinct protein pairs is almost N2/2.

So it stands to reason, just on a crude probabilistic estimate, that a minuscule change in a protein, due to a change of a single amino acid in its sequence, is far more likely to affect how the protein interacts with some other protein than how it significantly affects the protein's main function.

The net is that small phenotype-altering changes to existing genes are much more likely to result from changes to protein interactions than from development of entirely new genes.

Further reading:

Web of protein interactions reflects human complexity better than number of genes – very good 5/12/08 article on this research at Science News

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Moral choice: fairness, utility, and the insula

Sunday, May 18, 2008

We continue to learn more about the neuropsychological basis of moral thinking and moral emotions in humans:

Justice In The Brain: Equity And Efficiency Are Encoded Differently (5/8/08)
Which is better, giving more food to a few hungry people or letting some food go to waste so that everyone gets a share" A study appearing in Science finds that most people choose the latter, and that the brain responds in unique ways to inefficiency and inequity.

The study, by researchers at the University of Illinois and the California Institute of Technology, used functional magnetic resonance imaging (fMRI) to scan the brains of people making a series of tough decisions about how to allocate donations to children in a Ugandan orphanage.

There are two main issues regarding moral decision making here.

The first involves two separate principles often used in analyzing moral/ethical problems related to the distribution of goods within a group of people. (The group might be children in a family or different classes of people in a society, among many possibilities.) On one hand, it is generally regarded as "good" to maximize "equity" in moral decisions, so that some individuals are not favored over others without significant justification. (I prefer the term "fairness" for this.)

On the other hand, it is also regarded as "good" to maximize "efficiency", so that the greatest total amount of benefit accrues to a group as a whole. (I prefer the term "utility" for this.)

But these principles can come into conflict, and the research discussed here investigates a contrived, but sharp, example. Philosophers of ethics call such dilemmas the problem of "distributive justice".

The second issue concerns the style of thinking that a decision maker faced with this kind of dilemma does use, and also, perhaps, what style the decision maker "should" use. On one hand, the decider might try to systematically and logically apply some standard set of rules that are considered appropriate for the situation. But on the other hand, the decider might rely more on emotional factors that indicate what "feels right", the "gut feeling", about what seems "right" in a concrete situation.

Philosophers often describe these two alternatives as "cognitivist" vs. "sentimentalist". The former is sometimes associated with the philosopher Immanuel Kant, and the latter with David Hume.

What emerges from the research is (not surprisingly) that individual decision makers differ in the degree that they favor "equity" vs. "efficiency", and also whether they tend to rely more on logic or emotion to make their decisions.

More interestingly, most people normally process considerations of both equity and efficiency in order to reach a decision, but different parts of the brain are used for the two. Likewise, in making the decision, distinct parts of the brain which normally handle emotional or logical processing can become involved in processing the equity/efficiency trade-off.

One way to think of this is that there are separate calculations of both equity and efficiency that are made for each available choice. And then the result of those calculations are fed to separate subsystems to weigh the alternatives.

The different moral and ethical decisions that different people will arrive at can be attributed to individual differences as to how the various stages of the decision process are handled. For instance, an individual may favor equity over efficiency, and tend to use emotion rather than logic to reach the decision.

Here's what the study found:
In these trails, subjects overwhelmingly chose to preserve equity at the expense of efficiency, Hsu said. "They were all quite inequity averse." The findings support other studies that show that most people are fairly intolerant of inequity.

The animation, in conjunction with the fMRI, allowed the researchers to view activity in the brain at critical moments in the decision-making process. After analyzing the data, they found that different brain regions -- the insula, putamen and caudate -- were activated differently, and at different points in the process, Hsu said.

Activation of the insula varied from trial to trial in relation to changes in equity, while activity in the putamen corresponded to changes in efficiency, he said.

In contrast, the caudate appeared to integrate both equity and efficiency once a decision was made.

The role of the insula (or, more formally, insular cortex) is especially interesting, since this brain region has been associated with quite a few other types of social-emotional mental processing. We'll come back to that in a moment. But here are the conclusions of the researchers:
The involvement of the insula appears to support the notion that emotion plays a role in a person's attitude towards inequity, Hsu said.

The insula is known to play a key role in the awareness of bodily states and emotions. Studies have shown that it is activated in people experiencing hunger or drug-related cravings, and in those feeling intense emotions such as anger, fear, disgust or happiness. Other research has implicated the insula in mediating fairness. ...

Together, the results "show how the brain encodes two considerations central to the distributive justice calculus and shed light on the cognitivist/sentimentalist debate regarding the psychological underpinnings of distributive justice," the authors wrote.

Here's how another report about this research summed it up:

Your Brain on Ethics (5/8/08)
The fMRI scans contain hints of how these two factors might be encoded by the brain. The insula, a brain region linked to processing emotion, became more active when subjects considered more inequitable distributions of meals; it was also more active in subjects whose choices suggested a greater-than-average aversion to inequity. Activity in another region, the putamen, seemed to track the common good, rising in proportion to the total number of meals that could be donated in a given case.

Now let's have a quick overview of the insula. Turns out that it's involved in a lot more than just moral decision-making. Here's a general article from a bit over a year ago:

A Small Part of the Brain, and Its Profound Effects (2/6/07)
According to neuroscientists who study it, the insula is a long-neglected brain region that has emerged as crucial to understanding what it feels like to be human.

They say it is the wellspring of social emotions, things like lust and disgust, pride and humiliation, guilt and atonement. It helps give rise to moral intuition, empathy and the capacity to respond emotionally to music. ...

If it does everything, what exactly is it that it does?

For example, the insula “lights up” in brain scans when people crave drugs, feel pain, anticipate pain, empathize with others, listen to jokes, see disgust on someone’s face, are shunned in a social settings, listen to music, decide not to buy an item, see someone cheat and decide to punish them, and determine degrees of preference while eating chocolate.

Damage to the insula can lead to apathy, loss of libido and an inability to tell fresh food from rotten. ...

Of course, like every important brain structure, the insula — there are actually two, one on each side of the brain — does not act alone. It is part of multiple circuits.

The insula itself is a sort of receiving zone that reads the physiological state of the entire body and then generates subjective feelings that can bring about actions, like eating, that keep the body in a state of internal balance. Information from the insula is relayed to other brain structures that appear to be involved in decision making, especially the anterior cingulate and prefrontal cortices.

Stay tuned. We'll be discussing the insula quite a bit more here, I think.

Further reading:

  • The Right and the Good: Distributive Justice and Neural Encoding of Equity and Efficiency – Original research report published 5/8/08 at Science Express (sub. rqd. for full access)

  • Which Orphans Do You Want to Starve? – Blog article by Sharon Begley at Newsweek

  • How Fairness Is Wired In The Brain – 5/28/08 press release about the research dealing with fairness and the insula

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  • Cancer stem cells II

    Saturday, May 17, 2008

    Since we've just had a discussion of generalities about cancer stem cells (here), it seems like it would be fun to have a summary of research on CSCs that was presented at the recent meeting of the American Association for Cancer Research in San Diego, or reported since then. So here it is.

    As general background, keep in mind that cell surface proteins CD44 and CD24 are considered to be markers of cancer stem cells in various (but not necessarily all) types of cancer. Also, certain cell signaling pathways are thought to be especially important in the activity of cancer stem cells. The list includes Wnt, Sonic hedgehog, Notch, and Bmi1.

    Stem Cell-Like Cancer Cells Resistant To Standard Therapy, Responsive To Targeted Therapy (4/29/08)
    Previous research had identified a subset of cells in breast tumors that have the ability to form colonies in culture and give rise to tumors in mouse models. Such cells are thought to be cancer stem cells. They express the cell surface glycoprotein CD44, but not CD24, and they appear to be resistant to standard chemotherapeutic agents. However, the drug lapatinib, which inhibits the HER2 pathway, seems to selectively kill these cells.

    Getting To The Roots Of Breast Cancer (4/29/08)
    This is another report on the research described in the previous item. It provides additional details on the research protocol.

    Stem Cell Type Supposed To Be Crucial For Angiogenesis And Cancer Growth Does Not Exist? (4/22/08)
    This study casts doubt on the existence of a certain type of bone-marrow derived stem cell that has been suspected of circulating in the blood and acting as a precursor to endothelial cells that make up blood vessel walls. Such cells, if they existed, would be an important target for inhibiting angiogenesis in tumors. The researchers showed, using advanced techniques with mouse models, that endothelial differentiation is not a typical function of bone-marrow derived stem cells.

    Ovarian Cancer Stem Cells Identified, Characterized (4/17/08)
    Researchers have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer's recurrence and its resistance to chemotherapy. They isolated cells from samples of either peritoneal fluid or solid tumors. The cancer stem cells that were identified had traditional cancer stem cell markers including CD44 and MyD88 (which interacts with toll-like receptors to activate NF-κB).
    The cells also showed a high capacity for repair and self-renewal. Such cells, when isolated, were capable of forming tumors 100 percent of the time. Within those tumors, 10 percent of the cells were CD44 positive, while 90 percent were CD44 negative, indicating that some cancer stem cells had undergone differentiation.

    Stem Cells: The Role Of Cancer-initiating Cells In Diagnosis And Treatment (4/15/08)
    This press release describes research presented at the AACR meeting related to stem cells and pancreatic, bladder, ovarian, and breast cancer, and glioma.

    Research in pancreatic cancer found that in addition to CD44 and CD24, the enzyme aldehyde dehydrogenase was expressed in a small population of tumor cells. Cells expressing aldehyde dehydrogenase had greater growth capacity than those that didn't, and they were also associated with poorer overall survival.

    In a study of breast cancer and glioma, surface markers were not found be sufficient as markers of stem cell activity. However, cells with low proteasome activity did have notably greater capacity for self-renewal and tumor production capacity. (Proteasomes are large protein complexes that degrade unneeded or damaged proteins.)

    Researchers studying bladder transitional cell carcinomas found, in 40% of cases, CD44+ cells with other stem cell self-renewal patterns. In these cells, 85% had active Gli1, a part of the Hedgehog pathway, originally discovered in human glioblastoma. A relatively small percentage had active Bmi1, Stat3, or β-catenin (part of the Wnt pathway). None had active Oct4 or Nanog (pluripotent stem cells markers).

    The research on ovarian cancer (noted above) involving CD44 and MyD88 markers is referenced again here.

    Stem Cell Marker Controls Two Key Cancer Pathways (4/14/08)
    Research into breast cancer stem cells has identified, for the first time, another gene that may be involved, Msi1. The investigators showed that Msi1 activated Wnt and Notch signaling. Other studies have shown that Msi1 is a marker of human adult stem cells in general because it has been found in human breast, colon, brain, skin, and other cells. Msi1 was found to affects mammary cells to influence whether they develop into muscle, milk duct linings, etc. Further, Msi1 was found to be expressed in particularly aggressive tumors.

    Stem Cells And Cancer: Scientists Investigate A Fine Balancing Act (4/11/08)
    This is a report of a general talk about how the mechanisms normally involved in balancing different functions of stem cells may also contribute to cancer. For example, research shows that Bmi1 is important for maintaining stocks of stem cells, and without it stocks of stem cells are depleted. But also Bmi1 is overactive in various cancers including brain tumors.

    Secrets of cellular signaling shed light on new cancer stem cell therapies (4/10/08)
    Researchers are beginning to study inhibition of signaling pathways that seem to be active in tumors fed by cancer stem cells. In this case, inhibition of the Notch pathway is being investigated as part of a treatment, together with chemotherapy, for metastatic breast cancer. An important question is whether cancer stem cells are sufficiently different from normal adult stem cells so that inhibition of Notch signaling is not harmful. Results of testing in mice indicate that Notch signals are not required for the maintenance of blood-forming stem cells in adult mice.

    Stem cells and cancer: cancer pathways that also control the adult stem cell population (4/10/08)
    Apc (adenomatosis polyposis coli) is a tumor-suppressing protein that controls β-catenin and hence affects Wnt signaling. When intestinal crypts are damaged and need to be regenerated, Wnt signaling directs stem cells to generate replacement cells. Apc normally turns off Wnt signaling of stem cells when it is no longer needed. The research here showed that if Apc is lost or damaged, Wnt signaling may continue and result in tumor formation

    Cancer Stem Cells Created With New Technique (4/9/08)
    One of the most important unresolved questions about cancer stem cells is how they originate to begin with. For instance, are they mutations of existing stem cells, or instead precancerous cells that have acquired stem-cell-like capabilities? The research here supports the latter scenario. Starting with normal skin cells, the researchers activated three genes associated with embryonic stem cells. The result closely resembled known cancer stem cells. And they also had more resemblance to normal embryonic stem cells than to normal adult stem cells. One of the genes was Myc, which has also been used to create pluripotent stem cells from skin cells. In addition to the scientific significance of this work, it should also facilitate study of cancer stem cells, which are otherwise hard to locate.

    Module Map Links Embryonic Stem Cells And Cancer Stem Cells (4/9/08)
    The researchers involved in the work described in the preceding report have additional related findings. They systematically compared gene expression patterns between embryonic stem cells and multiple types of human cancer cells. Gene expression patterns in diverse human epithelial cancers were much like patterns in embronic stem cells. Further, presence of these patterns in cancer cells strongly predicted metastasis and death. On the other hand, normal adult tissue stem cells had an opposite pattern, which was repressed in various human cancers compared to normal tissues. The researchers additionally demonstrated that c-Myc, but not other oncogenes, was sufficient to reactivate the ESC-like program in normal and cancer cells.

    And here's some earlier research that features the Nanog and Bmi1 proteins:

    To Evade Chemotherapy, Some Cancer Cells Mimic Stem Cells (9/19/07)
    Anti-cancer treatments often effectively shrink the size of tumors, but some might have an opposite effect, actually expanding the small population of cancer stem cells believed to drive the disease, according to new findings.

    "Our experiments suggest that some treatments could be producing more cancer stem cells that then are capable of metastasizing, because these cells are trying to find a way to survive the therapy," said one of the study's investigators, Vasyl Vasko.

    When the researchers applied various anti-cancer drugs to experimental cancer cells, they found that surviving cells expressed more Nanog and Bmi1:
    They selected a rare form of cancer, mesenchymal chondrosarcoma (MCS), which has not been well described and for which there is no effective treatment. The researchers first determined that Nanog and BMI1 stem cell markers were more highly expressed in metastatic tumors compared to primary tumors. ...

    They then applied various therapies - from VEGF inhibitors such as Avastin to the proteasome inhibitor Velcade - in mice implanted with human MSC, and analyzed the effects on tumors. Some of the treatments seemed to work, because they led to a dramatic decrease in the size of the tumors, Dr. Vasko said. But analysis of stem cell expression before and after treatment revealed that even as some anti-cancer treatments shrank tumors, they increased expression of Nanog and BMI1. "These treatments were not enough to completely inhibit tumor growth, and the cancer stem cell markers were still present," Dr. Vasko said.

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    What Pinker said

    Wednesday, May 14, 2008

    The Stupidity of Dignity
    To understand the source of this topsy-turvy value system, one has to look more deeply at the currents that underlie the Council. Although the Dignity report presents itself as a scholarly deliberation of universal moral concerns, it springs from a movement to impose a radical political agenda, fed by fervent religious impulses, onto American biomedicine.

    The report's oddness begins with its list of contributors. Two (Adam Schulman and Daniel Davis) are Council staffers, and wrote superb introductory pieces. Of the remaining 21, four (Leon R. Kass, David Gelernter, Robert George, and Robert Kraynak) are vociferous advocates of a central role for religion in morality and public life, and another eleven work for Christian institutions (all but two of the institutions Catholic). Of course, institutional affiliation does not entail partiality, but, with three-quarters of the invited contributors having religious entanglements, one gets a sense that the fix is in. A deeper look confirms it.

    Here's Pinker citing an especially choice quote from Leon Kass, the high-guru of right-wing "bioethics"
    Kass has a problem not just with longevity and health but with the modern conception of freedom. There is a "mortal danger," he writes, in the notion "that a person has a right over his body, a right that allows him to do whatever he wants to do with it." He is troubled by cosmetic surgery, by gender reassignment, and by women who postpone motherhood or choose to remain single in their twenties. Sometimes his fixation on dignity takes him right off the deep end:
    Worst of all from this point of view are those more uncivilized forms of eating, like licking an ice cream cone--a catlike activity that has been made acceptable in informal America but that still offends those who know eating in public is offensive. ... Eating on the street--even when undertaken, say, because one is between appointments and has no other time to eat--displays [a] lack of self-control: It beckons enslavement to the belly. ... Lacking utensils for cutting and lifting to mouth, he will often be seen using his teeth for tearing off chewable portions, just like any animal. ... This doglike feeding, if one must engage in it, ought to be kept from public view, where, even if we feel no shame, others are compelled to witness our shameful behavior.

    And here is my own take on Kass, from almost three years ago.

    This new 555-page report that Pinker writes about is just one more salvo in the right-wing war on science. Fortunately, their war is going about as well for them as their war in Iraq. And even more fortunately, the dimwits behind this nonsense seem to be on track to lose big at the polls this fall.

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    Cancer stem cells

    Sunday, May 11, 2008

    Cancer stem cells (CSCs) have been mentioned here before in passing – recently here, for example. But it's now time to direct particular attention to them.

    One reason is that a number of new experimental results concerning CSCs were presented last month at the American Association for Cancer Research meeting in San Diego.

    Another reason is that CSCs, like other stem cells, happen to utilize a number of the signaling pathways that are very interesting in connection with cancer, embryonic development, and various other cellular processes. The list includes Myc, Nanog, Notch, Sonic hedgehog (Shh), TOR, and Wnt. This is a rapidly developing field of research, and CSCs are right in the thick of things.

    There is also some overlap with the recent active work going on with induced pluripotent stem cells (IPSCs). For example, Myc and Nanog turn up in IPSC research.

    Finally, CSCs are also controversial (as is to be expected of any field that's in rapid flux) – and controversies are inherently interesting to read about.

    One of the controversies concerns whether CSCs really exist and are important to the extent their principal investigators tend to believe. A reason to be skeptical of their importance is that there are some indications that CSCs should not be too rare, and that they should also be largely resistant to standard chemotherapy drugs. Yet in many cancers, chemotherapy can kill at least 99% of tumor cells, which would therefore include most CSCs. But this reasoning, too, is controversial.

    But let's go back to first principles and explain just what a CSC is. Even that is tricky, since there are several models hypothesized for CSC behavior. In most general terms, however, a CSC is much like other adult stem cells, in that when a CSC divides, one daughter cell is an essentially similar CSC, while the other daughter is a more ordinary tumor cell, which does not have as much ability to proliferate by repeated division.

    This is already somewhat different from the older picture of cancer. In that picture, one "renegade" cell first acquires somehow a mutation of its DNA which defeats one of the numerous cellular safeguards against uncontrolled cell proliferation. As time goes on, descendants of that cell accumulate further mutations that defeat other safeguards. Eventually, a significant population of cells exists which have a similar set of mutations that can evade most of the safeguards, and at that point, a dangerous tumor starts to grow. In effect, most of the cells of the tumor are stem cells, which continually produce more of their kind, without serious inhibition.

    But it is gradually became clear that such a naive picture couldn't be generally correct. The main reason is that many cancerous cells stop dividing after awhile, and they are not capable of seeding a new tumor if (for instance) they are introduced into another part of an experimental animal having the tumor, or into a tumor-free animal. Most cells cannot divide an arbitrarily large number of times. There is a limit to the number of cell divisions, called the Hayflick limit. This limit, typically, is about 52 divisions. When the limit is reached, a cell does not necessarily die, but it does enter a new phase of life called the senescence phase, in which it ceases to divide.

    The main reason for the Hayflick limit is a structure, called a telomere, found at the ends of all chromosomes. Telomeres consist of repeated short segments of DNA and protect the chromosome from damage during cell division. But a telomere shortens each time a cell divides, and once it becomes too short, the cell becomes senescent. This is because the mechanisms that protect a cell's DNA normally do not permit the cell cycle to function when telomeres are too short. Even if these mechanisms could be evaded, the cell's DNA would be damaged in the division process, and the resulting malfunctions would likely cause the cell to die.

    However, stem cells need to be able to divide far beyond the Hayflick limit. Embryonic stem cells need this ability in order for an embryo to grow from a single cell into an organism with trillions of cells. Adult stem cells also need this ability to be able to replace cells in certain tissues that must be frequently renewed, such as in the skin and the lining of the intestines. In order to make this possible, stem cells express an enzyme, called telomerase, which has the specific function of rebuilding shortened telomeres.

    Many, but not all, cancer cells also express telomerase. Only those that do are capable of indefinitely dividing. So such cancer cells have the production of telomerase in common with stem cells. That still doesn't mean that they are CSCs, because they may lack other attributes of stem cells. In particular, they may not be able to produce at least one exact copy of themselves when dividing. Instead, both daughter cells may be more differentiated and specialized than the mother cell, and (among other things) lose the ability to produce telomerase. Once that happens, the daughter cells' fate is eventual senescence, at best.

    There are several possible ways in which CSCs might arise. One possibility is that all mutations necessary for a growing cancer occur, over a period of time, in a population of actual stem cells. (Once the mutations first occur, they of course are inherited by all descendants.) Another possibility is that only some of the mutations occur in the stem cell phase, while other mutations necessary for cancer occur after the full "stemness" is lost (but while the cells are still capable of repeated division). Perhaps a late stage of cancer development is that cells with enough oncogenic mutations to become cancerous reacquire an ability to divide repeatedly, if that was lost along the way.

    In fact, there is evidence that both of these models, and possibly others, actually occur. It all boils down to the time sequence of mutation events in a particular type of cancer, and the sequence is likely to be different in different types of cancer. In any case, one of the main tasks of cancer research now is to figure out not only what mutations occur in a particular type of cancer, but also the order in which they typically occur. The hope is that sufficient knowledge of this process will make it possible to devise ways to stop it.

    Here are some other things to read for additional background:

    Update, 5/17/08: I've written up some summaries of recent research on cancer stem cells here.

    Additional links:

    The Cancer Stem Cells Project

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    More problems with alternative energy

    Saturday, May 10, 2008

    It's certainly not encouraging to find research that casts doubt on the economic or technological viability of energy sources other than fossil fuels. There are two compelling reasons the whole world needs to transition away from fossil fuels: (1) To derive energy from fossil fuels requires combustion, which releases large amounts of the greenhouse gas CO2, and other pollutants, into the atmosphere. (2) Resources of the most convenient (for use in land vehicles and aircraft) fossil fuel – petroleum – are rapidly dwindling, especially in easily accessible locations, so the price will necessarily increase over time, as will the risk of armed conflict between countries to protect access.

    On the other hand, it's necessary to be as realistic as possible about the alternatives, in order to avoid heading down a path that could be (quite expensively) wrong.

    So in a couple of recent posts here and here I discussed various studies that raised cautions about the potential for solar energy, nuclear energy, hydrogen (for fuel cells), and biofuels. New cautionary reports about these various alternatives keep appearing.

    Let's begin with solar. There's more than one way to take advantage of energy from the Sun. Photovoltaic production of electricity directly from sunlight receives the most attention. But there are other approaches, such as solar thermal energy and perhaps (some day) even the use of artificial photosynthesis:

    Artificial Photosynthesis Moves A Step Closer (4/28/08)
    Imagine a technology that would not only provide a green and renewable source of electrical energy, but could also help scrub the atmosphere of excessive carbon dioxide resulting from the burning of fossil fuels. That’s the promise of artificial versions of photosynthesis, the process by which green plants have been converting solar energy into electrochemical energy for millions of years. To get there, however, scientists need a far better understanding of how Nature does it, starting with the harvesting of sunlight and the transporting of this energy to electrochemical reaction centers.

    But most commonly when "solar energy" is discussed, photovoltaic technology is what's actually meant. The technology has existed for many years. The problem has always been cost. Even today it's estimated to be almost ten times as expensive per kilowatt-hour to generate electricity with photovoltaics as it is from fossil fuel:

    Expert Foresees 10 More Years Of Research & Development To Make Solar Energy Competitive
    The single biggest challenge, Gray said, is reducing costs so that a large-scale shift away from coal, natural gas and other non-renewable sources of electricity makes economic sense. Gray estimated the average cost of photovoltaic energy at 35 to 50 cents per kilowatt-hour. By comparison, other sources are considerably less expensive, with coal and natural gas hovering around 5-6 cents per kilowatt-hour.

    Because of its other advantages -- being clean and renewable, for instance -- solar energy need not match the cost of conventional energy sources, Gray indicated. The breakthrough for solar energy probably will come when scientists reduce the costs of photovoltaic energy to about 10 cents per kilowatt-hour, he added. "Once it reaches that level, large numbers of consumers will start to buy in, driving the per-kilowatt price down even further. I believe we are at least ten years away from photovoltaics being competitive with more traditional forms of energy."

    Major challenges include developing cheap solar cells that work without deterioration and reducing the amounts of toxic materials used in the manufacture of these cells. But producing low cost photovoltaics is only a step in the right direction. Chemists also need to focus on the generation of clean fuels at costs that can compete with oil and coal.

    Nuclear power continues to be quite problematical too. Many of its problems have been known for a long time, such as the difficulty of safely disposing of spent fuel and the dangers of diversion of nuclear fuel to weapons. But more recently attention has begun to focus on the increasing cost of extracting and processing uranium, and the greenhouse gases generated in that process:

    Questioning Nuclear Power's Ability To Forestall Global Warming (4/30/08)
    Rising energy and environmental costs may prevent nuclear power from being a sustainable alternative energy source in the fight against global warming, according to a new study.

    In the article, Gavin M. Mudd and Mark Diesendorf investigate the "eco-efficiency" of mining and milling uranium for use as fuel in nuclear power plants. ...

    The study points out that supplies of high-grade uranium ore are declining, which may boost nuclear fuel's environmental and economic costs, including increases in energy use, water consumption and greenhouse gas emissions. In addition, newly discovered uranium deposits may be more difficult to extract in the future -- a further drain on economic and environmental resources.

    Here are two somewhat longer articles about this report, with some rebuttal from the uranium mining industry: Nuclear may lose green tag if fuel costs rise and Nuclear energy becoming less sustainable.

    Finally, it's often overlooked that there's one additional increasingly scarce resource that's usually needed to produce energy by many different technologies: fresh water.

    Water Needed To Produce Various Types Of Energy (4/17/08)
    It is easy to overlook that most of the energy we consume daily, such as electricity or natural gas, is produced with the help of a dwindling resource – fresh water. Virginia Tech professor Tamim Younos and undergraduate student Rachelle Hill are researching the water-efficiency of some of the most common energy sources and power generating methods.

    When the requirements for fresh water are considered, new disadvantages appear for many alternative energy sources, especially biofuels and nuclear energy:
    According to the study, the most water-efficient energy sources are natural gas and synthetic fuels produced by coal gasification. The least water-efficient energy sources are fuel ethanol and biodiesel.

    In terms of power generation, Younos and Hill have found that geothermal and hydroelectric energy types use the least amount of water, while nuclear plants use the most.

    Update, 5/14/08:

    More headaches of nuclear energy. There's a new, longish Scientific American article on the problem of nuclear fuel recycling: Nuclear Fuel Recycling: More Trouble Than It's Worth

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    Is DNA Repair A Substitute For Sex?

    Friday, May 9, 2008

    Yeah, it's a trick question. The answer is clearly "no" – unless you're a bdelloid rotifer.

    What's interesting, of course, about these minute but multi-cellular animals is that they are completely asexual, and apparently have been for millions of years. There are no males, and females reproduce entirely by parthenogenesis. Although that might seem to imply a rather joyless existence, it hasn't stopped the bdelloids from persisting, and even diversifying into more than 370 species.

    The conventional evolutionary reason for the invention and predominance of sexual reproduction – apart from the recreational aspect – is that it provides a mechanism for a species to cope with the inevitability of sustaining damage to its DNA. So why do the bdelloids seem to think they have a better way?

    Is DNA Repair A Substitute For Sex?
    These hardy creatures somehow escape the usual drawback of asexuality – extinction – and the MBL’s David Mark Welch, Matthew Meselson, and their colleagues are finding out how.

    In two related papers published recently in Proceedings of the National Academy of Sciences (PNAS), the team proposes an interesting hypothesis: Bdelloid rotifers have been able to give up sex and survive because they have evolved an extraordinary efficient mechanism for repairing harmful mutations to their DNA. ...

    In animals that do have sex, DNA repair is accomplished during meiosis, when chromosomes pair up (one from the father, one from the mother) and “fit” genes on one chromosome can serve as templates to repair damaged genes on the other chromosome. The bdelloid, though, always seems to reproduce asexually, by making a clone of itself. How then, does it cope with deleterious mutations?

    Before we come to the hypothesized answer, it must be noted that the bdelloids' ability to repair their DNA is not merely adequate. It's spectacularly good:
    MBL adjunct scientist Matthew Meselson and Eugene Gladyshev, both of Harvard University, demonstrate the enormous DNA repair capacity of bdelloid rotifers by zapping them with ionizing radiation (gamma rays), which has the effect of shattering its DNA into many pieces. “We kept exposing them to more and more radiation, and they didn’t die and they didn’t die and they didn’t die,” says Mark Welch. Even at five times the levels of radiation that all other animals are known to endure, the bdelloids were able to continue reproducing.

    “Because there is no source of such intense ionizing radiation on Earth, except if we make it, there is no way these organisms could have evolved to be radiation resistant,” says Mark Welch. Instead, they propose that bdelloids’ DNA repair capacity evolved due to a different environmental adaptation – tolerance of extreme dryness.

    Bdelloids, which live in ephemeral aquatic habitats such as temporary freshwater pools and on mosses, are able to survive complete desiccation (drying out) at any stage of their life cycle. They just curl up and go dormant for weeks, months, or years, and when water becomes available, they spring back to life. Mark Welch and his colleagues showed that desiccation, like ionizing radiation, breaks up the rotifers’ DNA into many pieces. Presumably, the same mechanisms they use to survive desiccation as part of their life cycle also protect them from ionizing radiation.

    Hmmmm. That sounds oddly familiar. Where have we heard about that sort of thing before? Oh yes, this is apparently exactly the same thing found in a bacterium (Deinococcus radiodurans), as discussed here. And in the closely related bacterial species, Deinococcus geothermalis, as discussed here.

    But what the bdelloids do is much more impressive, since they are multicellular eukaryotes, not simple prokaryotic bacteria. In any case, what't the trick for bdelloids?
    One feature that may confer exceptional DNA repair capacity on the bdelloids is described in the team’s second PNAS paper. Here, they give evidence that the bdelloid rotifer, like most animals, originally had two copies of each chromosome. But at some point in its evolution, it underwent a “whole-genome duplication,” giving it four copies of each chromosome and hence of each gene. Normally, lineages that undergo whole-genome duplication lose the duplicate genes over time. The bdelloid, though, has kept most of its duplicate genes throughout its evolutionary history.

    “We believe they have kept most of their duplicate genes because they are serving as templates for DNA repair,” says Mark Welch.

    The amino acid chirality mystery

    Sunday, May 4, 2008

    If the analysis here is correct, it solves one of the more puzzling mysteries of life on Earth – namely, the fact that all 20 amino acids found in biological proteins are "left-handed".

    Meteorites Delivered The 'Seeds' Of Earth's Left-hand Life, Experts Argue
    In a report at the 235th national meeting of the American Chemical Society, Ronald Breslow, Ph.D., University Professor, Columbia University, and former ACS President, described how our amino acid signature came from outer space.

    Chains of amino acids make up the protein found in people, plants, and all other forms of life on Earth. There are two orientations of amino acids, left and right, which mirror each other in the same way your hands do. This is known as "chirality." In order for life to arise, proteins must contain only one chiral form of amino acids, left or right, Breslow noted.

    "If you mix up chirality, a protein's properties change enormously. Life couldn't operate with just random mixtures of stuff," he said.

    Recall that a carbon atom can form up to four bonds with other atoms. (Sometimes there are 2 or more bonds with the same atom, such as a double bond to another carbon atom.)

    You can imagine these bonds arranged in a tetrahedral shape, that is, from a central carbon atom in the direction of the 4 vertices of a tetrahedron. In an amino acid, three of the bonds are occupied by a hydrogen atom, an amino group (NH2), and a carboxyl group (COOH). The remaining bond is occupied by a fourth group, which is variable (but there are only 20 possibilities that normally occur in Earthly biology) and determines the specific amino acid. The simplest amino acid is glycine, in which the fourth bond is occupied by a single hydrogen atom.

    If you think of the amino acid as a tetrahedron, with the carboxyl group at the top, the other three components are arranged around the three bottom vertices. In glycine, two of those positions will be hydrogen atoms. But in all other amino acids, there are two different orders in which the distinct components can be arranged. Think of the tetrahedron's axis running from the central carbon atom to the top. If you look down that axis towards the base of the tetrahedron, then the hydrogen atom will be in either the clockwise or counterclockwise direction from the amino group. The latter is (by convention) called the left-handed (L) version, and the former is called the right-handed (R) version.

    A protein is a series of amino acids tied together by peptide bonds, which form between the amino group of one amino acid and the carboxyl group of the other (with an H2O molecule removed, since an H pairs with an OH). In biological proteins such bonds form only between amino acids of the same chirality (both R or both L). So all proteins must consist only of L or R amino acids. As it happens, only the L type of protein occurs in nature on Earth. Presumably that is because at some time back when life was first developing, L amino acids significantly outnumbered R amino acids, and hence L proteins predominated over R proteins.

    So the mystery is reduced to that of why at some point in time there were many more L amino acids than the R form. It has been shown that amino acids can form spontaneously from inorganic materias under some conditions (the Miller-Urey experiments demonstrated this.) However, one would expect equal amounts of R and L amino acids under such circumstances.

    But there's another way out, because we know that in fact amino acids can form in interstellar space, since they were found in parts of the Murchison meteorite (and later others) that were uncontaminated with Earthly material. Furthermore, there's one definite way that amino acids which existed originally in an equal mixture of L and R forms on a chunk of rock hurtling through space could have their proportion tilted in one direction or the other:
    These amino acids "seeds" formed in interstellar space, possibly on asteroids as they careened through space. At the outset, they have equal amounts of left and right-handed amino acids. But as these rocks soar past neutron stars, their light rays trigger the selective destruction of one form of amino acid. The stars emit circularly polarized light--in one direction, its rays are polarized to the right. 180 degrees in the other direction, the star emits left-polarized light.

    All earthbound meteors catch an excess of one of the two polarized rays. Breslow said that previous experiments confirmed that circularly polarized light selectively destroys one chiral form of amino acids over the other. The end result is a five to ten percent excess of one form, in this case, L-amino acids. Evidence of this left-handed excess was found on the surfaces of these meteorites, which have crashed into Earth even within the last hundred years, landing in Australia and Tennessee.

    So, one asks, is it possible that this imbalance of R and L amino acids was transferred from a meteorite to prebiotic Earth? In a series of experiments Breslow confirmed that this could happen:
    Breslow simulated what occurred after the dust settled following a meteor bombardment, when the amino acids on the meteor mixed with the primordial soup. Under "credible prebiotic conditions"-- desert-like temperatures and a little bit of water -- he exposed amino acid chemical precursors to those amino acids found on meteorites.

    Breslow and Columbia chemistry grad student Mindy Levine found that these cosmic amino acids could directly transfer their chirality to simple amino acids found in living things. Thus far, Breslow's team is the first to demonstrate that this kind of handedness transfer is possible under these conditions.

    On the prebiotic Earth, this transfer left a slight excess of left-handed amino acids, Breslow said. His next experiment replicated the chemistry that led to the amplification and eventual dominance of left-handed amino acids.

    That's where things stand now. We have as yet no way of knowing whether this is the scenario that actually occurred. But it is the most credible scenario yet devised to explain the otherwise astonishing fact that essentially all life on Earth uses only left-handed amino acids.

    Further reading:

    Meteorite source for life's handedness (4/8/08)

    Did a Cooked Meteorite Seed Life on Earth? (4/6/08)


    Searching for dark energy... at the South Pole

    Saturday, May 3, 2008

    Not all experimental astrophysical studies require elaborate, incredibly expensive equipment deployed at the L2 Sun-Earth Lagrangian point, like WMAP. A lot can be done with a microwave antenna just 10 meters across... if it's located at the South Pole.

    Cosmologists Probe Mystery Of Dark Energy With South Pole Telescope
    What can the SPT tell us about the past and future of dark energy? John E. Carlstrom, director of KICP and the S. Chandrasekhar Distinguished Professor in Astronomy and Astrophysics at the University of Chicago, says the telescope is examining clusters of galaxies to learn what role dark energy played in their evolution. “One of the important things we need to learn about dark energy is what influence it has had on structure,” Carlstrom says. If scientists can learn how the density of clusters changed over time, he says they can determine “constraints on the equation of state of dark energy.” That is, they can get a more precise idea of whether dark energy is taking us toward a big rip, a big crunch or something in between.

    The telescope is looking specifically for the Sunyaev-Zel’dovich (SZ) effect, a distortion of the CMB radiation caused by the highly energized gas of galaxy clusters. When photons originating from the CMB traverse the clusters, they interact with electrons and tend to scatter, creating slight variations in temperature -- shadows against the microwave background – that the SPT detects with a battery of 1,000 sensors chilled to near absolute zero.

    The SPT will survey about a fifth of the entire southern sky and is expected to detect thousands of clusters. Analyzing follow-up data from optical telescopes, the scientists will determine the mass, distance and age of the clusters. They will then map the clusters in space and time to see how their density and structure evolved over billions of years under the competing pulls of gravity and dark energy. They hope to learn how much power dark energy exerted in the early universe, how it evolved to dominate the universe now, and by extension, how much power it may wield in the future.

    But the SPT isn't adapted only for studies of dark energy. As a sensitive microwave telescope, it can also make detailed observations of the cosmic microwave background, much as WMAP does.
    The SPT’s activity will not end with this survey of galaxy clusters. Another project in the works will use the telescope to scan the CMB for tiny fluctuations in its polarization. Like visible light, the microwave radiation from the Big Bang has waves moving in electromagnetic fields at different angles, some up-and-down and other side-to-side. Observations with another South Pole instrument, the degree angular scale interferometer (DASI), have confirmed that the CMB is polarized as expected from prevailing theories about the physics of the Big Bang. Researchers now want to use the more sensitive SPT to look for minute variations in the CMB polarization that mark the presence of huge gravity waves.

    Stephan Meyer, associate director of KICP and Professor in Astronomy and Astrophysics at the University of Chicago, says these waves are “a reasonable fraction of the size of the universe” in length and would have been generated in the “inflationary epoch” of the Big Bang. This was the time when the universe was just 10-50 seconds old and matter had not yet coalesced into neutrons and protons. “We don’t really understand the physics of that era,” Meyer says. A new set of sensors, able to detect polarization as well as heat, is being built by the University of Chicago and should be ready for installation on the SPT by the austral summer (the northern winter) of 2009-10.

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    Trading sex for resources

    The title really says it all. Not much further commentary needed. Care for another example? How about bower birds?

    Just Like Penguins And Other Primates, People Trade Sex For Resources
    Female penguins mate with males who bring them pebbles to build egg nests. Hummingbirds mate to gain access to the most productive flowers guarded by larger males.

    New research shows that even affluent college students who don't need resources will still attempt to trade sexual currency for provisions, said Daniel Kruger, research scientist at the University of Michigan School of Public Health.

    The exchange of resources for sex---referred to by scientists as nuptial gifts---has occurred throughout history in many species, including humans, Kruger said. The male of the species offers protection and resources to the female and offspring in exchange for reproductive rights. For example, an arranged marriage can be considered a contract to trade resources.

    However, the recent findings suggest that such behaviors are hard wired, and persist no matter how much wealth, resources or security that people obtain.


    Finding The Higgs Boson

    Continuing this theme of stuff that attracts skeptics, how about the Higgs boson? As of right now, it really is just hypothetical. There's no observational evidence for it – but check back in a year or so.

    In the meantime, here's a good short summary of the observations that physicists need to make, and when something might turn up.

    Finding The Higgs Boson
    The Higgs’ ministrations are usually hidden away in the vacuum, but if enough energy is brought to bear in a tiny volume of space---at the point where two energetic particles collide---then the Higgs can be turned into an actual particle whose existence can be detected. Theoretical calculations made using the standard model of particle physics combined with previous experiments serve to limit the possible range of masses for the Higgs particle. Right now that mass is thought to be larger than 114 GeV but smaller than about 190 GeV.

    And in spite of all the publicity that the Large Hadron Collider is getting, the discovery could actually be made as a result of experiments which are already ongoing at the Tevatron:
    The Tevatron delivers more than enough energy to create a particle in that energy range. The main issue, then, is luminosity, or the density of beam particles crashed together per second. The Tevatron recently established a record high luminosity: 3.1 × 1032 per cm2 per second. What would a Higgs event look like? One speaker at the meeting, Brian Winer (Ohio State), said that the “most Higgs-like Higgs event” seen so far was one in which (it is surmised) the proton-antiproton collision at the Tevatron had created a fireball which then decayed into a W boson (one of the carriers of the weak nuclear force) and a Higgs particle.

    Special issue of General Relativity and Gravitation on dark energy

    Speaking of astrophysical theories that still have many skeptics, how about dark energy? Whatever your opinion of the theory, here's a real treasure trove of information – a whole issue of the journal General Relativity and Gravitation, and all the articles are available for free. But for how long I don't know, so better go get it now:

    General Relativity and Gravitation: Special issue on dark energy

    From the introduction:
    General Relativity and Gravitation has put together a special issue on “dark energy” in cosmology, because it is a major challenge to gravitational physics and actually to all of theoretical physics. We look at the observational side (the astrophysical data for dark energy and alternative explanations of that data), phenomenological models for dark energy and possible tests of these models, and the quantum gravity side (why do we expect a very large cosmological constant? what are the possible explanations of why it is small?). The idea is not to pursue one particular approach to this important problem, but rather to produce a survey of significant approaches that have been taken as regards each of its aspects.

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    Black holes exist

    It may come as a surprise to lay readers to learn that even as recently as 10 years ago there were prominent physicists who still doubted the existence of black holes.

    For example, there's Sir John Maddox, a trained chemist and physicist who was editor of Nature for 22 years. In a book published in 1998 (What Remains to be Discovered), he wrote, "The concept of black holes raises serious difficulties of a philosophical character." (p. 43) (Remember what C. F. Gauss said about philosophers.) And, "The habit of others in referring to black holes as "putative" seems to imply a collective uneasiness about the concept." (p. 112)

    But recent skeptics of black holes are in good company. Einstein, for one, vigorously objected to the idea. Around 1935 Subrahmanyan Chandrasekhar, later a Nobel Prize winner and now celebrated, but only in his mid-20s at the time, had the audacity to argue that black holes might form from collapsed stars only 1.44 times as heavy as the Sun – and nearly had his career wrecked from Sir Arthur Eddington's sharp criticism.

    Even very recently one still sees theoretical studies – such as reported here, here, here, here, here, here – that offer alternatives to the standard relativisic model of black holes.

    Nevertheless, to the consternation of skeptics, the evidence for the correctness of the standard model of black holes just continues to pile up:

    Quasar tests general relativity to the limit
    [T]eam leader Mauri Valtonen of Tuorla Observatory in Finland claims the work provides the first hard evidence for black holes, which are so massive that space–time is predicted to completely curve in on itself: "People refer to the concept of black holes all the time, but strictly speaking one first has to prove that general relativity holds in strong gravitational fields before we can be sure that black holes exist," he told physicsworld.com.

    And actually, the more significant part of that research is its validation of general relativity in very strong gravitational fields:
    Astronomers have obtained the most compelling evidence yet that massive objects dramatically warp space–time, as predicted by Einstein's general theory of relativity. Although the geometric nature of gravity was first demonstrated in 1919, when Arthur Eddington famously detected the subtle warping effect of the Sun on the light from distant stars, the new results provide the first test of Einstein's theory in much stronger gravitational fields.

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    Resveratrol and cancer

    Resveratrol is not a very new story these days. (For some earlier news, see here.) It is primarily known as an anti-oxidant and activator of sirtuins, but it has also been found to have specific anti-cancer properties, at least for pancreatic cancer:

    Mounting Evidence Shows Red Wine Antioxidant Kills Cancer (3/25/08)
    Rochester researchers showed for the first time that a natural antioxidant found in grape skins and red wine can help destroy pancreatic cancer cells by reaching to the cell's core energy source, or mitochondria, and crippling its function.

    The new study also showed that when the pancreatic cancer cells were doubly assaulted -- pre-treated with the antioxidant, resveratrol, and irradiated -- the combination induced a type of cell death called apoptosis, an important goal of cancer therapy.

    The fact that resveratrol has effects on the mitochondria of cancer cells is particularly interesting, since mitochondria are known to play an important role in apoptosis. One of the main ways cancer therapies such as radiation and chemotherapy kill cancer cells is by inducing apoptosis. However, advanced cancers develop ways of evading apoptosis. (See here.) If resveratrol independently interferes with the function of the mitochondria in cancer cells, that would be helpful.

    In fact, the research indicated several relevant effects of resveratrol:
    Laboratory experiments showed that resveratrol:

    • Reduced the function of proteins in the pancreatic cancer cell membranes that are responsible for pumping chemotherapy out of the cell, making the cells chemo-sensitive.
    • Triggered the production of reactive oxygen species (ROS), which are substances circulating in the human body that have been implicated in a number of diseases: when ROS is increased, cells burn out and die.
    • Caused apoptosis, which is likely the result of increased ROS.
    • Depolarized the mitochondrial membranes, which indicates a decrease in the cell's potential to function. Radiation alone does not injure the mitochondrial membrane as much.

    More: Red wine compound may kill pancreatic cancer cells (4/14/08)

    In related news, it may be worth noting that the biotech company called Sirtris, which has been developing enhanced therapeutic forms of resveratrol, recently entered into an agreement to be acquired by the pharmaceutical company GlaxoSmithKline. (See here, here, here.) This shows that the therapeutic potential of resveratrol, and other sirtuins – at least at this early stage – looks promising.

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    NF-κB and the hypoxic response

    It seems as though the NF-κB transcription factor is turning up all over the place these days. Recent examples are in relation to the harmful effects of avian flu infection (here) and protection of cells from apoptosis due to radiation (here).

    Now, the reason NF-κB is involved in the disasterous response of a person's lungs to the H5N1 virus is that it's a transcription factor affecting a number of immune system proteins. But a surprising recent discovery is that it also, independently of the immune system function, affects a cell's response to low oxygen conditions (hypoxia).

    Researchers Link Master Regulator Of Innate Immunity To The Hypoxic Response
    Survival of all animals depends on their ability to withstand microbial infections and adapt to fluctuations in oxygen concentrations. These abilities depend on two ancient, evolutionary gene expression responses called the innate immune response and the hypoxic response. In a new study published in the advanced online edition of the journal Nature on April 23, researchers at the University of California, San Diego School of Medicine reveal that a single protein is essential to both responses. This understanding may lead to new therapies to boost the body's immune function or to limit inflammatory damage in tissues deprived of oxygen.

    The research, led by Michael Karin, Ph.D., professor of pharmacology in UCSD's Laboratory of Gene Regulation and Signal Transduction, shows that transcription factor NF kappa Β (NF-κΒ) -- previously known for its role as the master regulator of the innate immune response -- is also a critical regulator of the hypoxic response.

    The hypoxic response consists of several survival measures that a cell takes to continue producing energy when its oxygen supply is curtailed. This happens, for example, in brain cells as a result of a stroke. One of the main parts of the response is switching energy production in the cell from the citric acid cycle to the less efficient process called glycolysis.

    A family of transcription factors called, naturally enough, hypoxia-inducible factors regulate the hypoxic response. In particular, the master regulator is known as HIF-1α. Well, guess what, it turns out that HIF-1α is dependent on NF-κB.
    More than ten years ago, the Karin lab identified an enzyme called IκΒ kinase beta (IKKβ) as the critical activator of NF-κΒ. In this study, the UCSD researchers interfered with activation of NF-κΒ by inactivating IKKβ in different cells and tissues of a laboratory mouse. When they examined how macrophages deficient in IKKβ responded to bacterial infections or oxygen deprivation, the researchers found that, in addition to the expected defect in activation of NF-κΒ, the macrophages also failed to accumulate HIF-1α, the master regulator of the hypoxic response. HIF-1α is normally accumulated in cells experiencing low ambient oxygen, or hypoxia; in turn, it activates several genes responsible for generating energy to allow cell survival. ...

    "The hypoxic response is important in order for macrophages and other immune cells to kill and eliminate bacteria. The surprising result of the new study is the discovery that HIF-1α accumulation is dependent on activation of NF-κΒ," said Karin.

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    Avian flu

    Friday, May 2, 2008

    Avian flu doesn't seem to be in the news so much these days, even though it continues to cause a steady stream of new human infections and often fatalities. The most heavily affected country continues to be Indonesia, but other countries that have this year reported avian flu in many domestic birds, and sometimes resulting human deaths, include Egypt, Turkey, India, Pakistan, Bangladesh, Vietnam, China, and South Korea.

    An encouraging recent development is that the mechanism responsible for the serious havoc that H5N1 causes in a person's lungs is becoming better understood. It turns out to involve a signaling cascade initiated by toll-like receptor 4 (TLR-4) on the surface of macrophages in the lungs.

    Macrophages are leukocytes (white blood cells) that play a role in both innate and acquired immunity. Among other things, under certain circumstances, they can cause prolific production of inflammation-causing cytokines, such as interleukin-1. When produced excessively cytokines trigger "cytokine storms" (see here), which seem to be the major harmful effect of H5N1 infection. Recently reported research gives more detail:

    A single pathway for lung damage
    TLR-4 is an important receptor in innate immunity, which signals activation via two pathways, TRIF and MyD88. The researchers found that lung injury was mediated exclusively through the TRIF pathway and not via MyD88. Also, the trigger for TLR-4 turned out to be the oxidation of the animals' own lung surfactant, made up of phospholipids. The oxidized phospholipids activates TLR-4, resulting in the cytokine storm that causes much of the lung damage. In order to see whether their results held true outside of the mouse-ICU, researchers tested human and simian lung samples infected with SARS, H5N1, anthrax and monkey pox and found the oxidized phospholipids in each case.

    One of the interesting end results of the TRIF pathway is the activation of the NF-κB transcription factor, which in turn upregulates other proteins that stimulate T cell production, inflammation, and other additional immune response.

    More: New Strategies Against Bird Flu

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