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Stress and weight gain

Monday, July 30, 2007

There is, apparently, truth to the idea that people under stress may gain weight – and it's not just that people simply choose to escape their problems by eating. And this is only one of the reasons stress isn't good for your general health.

Scientists Discover Key To Manipulating Fat; Pathway Also Explains Stress-induced Weight Gain
In the paper, the Georgetown researchers describe a mechanism they found by which stress activates weight gain in mice, and they say this pathway -- which they were able to manipulate -- may explain why people who are chronically stressed gain more weight than they should based on the calories they consume.

The key to the process that was found is a peptide (small protein) neurotransmitter called neuropeptide Y (NPY). NPY is produced under conditions of stress, as a by-product of the "fight-or-flight" response mediated by the sympathetic nervous system. An animal under conditions of chronic stress will have higher levels of NPY. The hormone was discovered 25 years ago, and earlier research indicates that it acts in the brain to increase appetite. (Although other aspects of the response may suppress appetite, which is why some overly stressed people may be emaciated.) The appetite-suppressing hormone leptin acts by inhibiting the activity of neurons that contain NPY.

What the new research found, however, is that, more importantly, NPY, acting outside the brain in adipose tissue, also alters an animal's metabolism to increase storage of fat:
As part of the study, Zukowska and her team examined the effect of several forms of chronic stress that mice in the wilderness can encounter, such as exposure for an hour a day over a two-week period to standing in a puddle of cold water or to an aggressive alpha mouse, and they conducted the experiments in combination with a regular diet or with a high-fat, high-sugar diet. Stressed animals fed a normal diet did not gain weight, but stressed mice given a high-fat diet did. In fact, the researchers found these mice put on more weight than expected given the calories they were consuming.

"They gained twice as much fat as would be expected, and it was all in their belly area," Kuo said. Stressed versus non-stressed animals ate the same amount of food, but the stressed animals processed it differently, she said, explaining, "the novel finding here is that NPY works on fat tissue, not in the brain."

In part, the research showed that NPY experimentally delivered in a mouse activated a G-protein coupled receptor called (naturally) a neuropeptide Y2 receptor (Y2R). (This is just one of 5 known NPY receptors.) Activation of Y2R was observed to promote storage of fat in adipose tissue:
[The] pathway involves two players -- a neurotransmitter (neuropeptide Y, or NPY) and the receptor (neuropeptide Y2 receptor, or Y2R) it activates in two types of cells in the fat tissue: endothelial cells lining blood vessels and fat cells themselves. In order to add fat selectively to the mice they tested, researchers injected NPY into a specific area. The researchers found that both NPY and Y2R are activated during stress, leading to apple-shape obesity and metabolic syndrome.

So NPY can lead to increased fat storage. But the converse is, happily, also true: blocking the NPY receptor shrinks fat:
Both the weight gain and metabolic syndrome, however, were prevented by administration of Y2R blocker into the abdominal fat.

Metabolic syndrome, you recall, comprises several undesirable elements, such as hyperglycemia, high blood pressure, central obesity, decreased HDL cholesterol, and elevated triglycerides. All of these can lead to more serious health problems, such as diabetes and cardiovascular disease. So there is the possibility that blocking Y2R could be beneficial to humans:
"We are hopeful that these findings might eventually lead to control of metabolic syndrome, which is a huge health issue for many Americans," [the study's senior author, Zofia Zukowska] said. "Decreasing fat in the abdomen of the mice we studied reduced the fat in their liver and skeletal muscles, and also helped to control insulin resistance, glucose intolerance, blood pressure and inflammation. Blocking Y2R might work the same way in humans, but much study will be needed to prove that."

Another account of this research reports expressions of optimism for development of human drugs to control stress-induced health problems:

Stress can be fattening, study finds
Mary F. Dallman of UC San Francisco said in an editorial in the same journal: "A large gap in our understanding of how chronic stressors lead to abdominal obesity has been filled…. Their results were remarkable and have profound implications for new drug development."

But it's not a sure thing. There is another hormone, called PYY, Pancreatic Peptide YY, or Pancreatic Peptide YY3-36. PYY is structurally similar to NPY and in fact can activate some NPY receptors. It has been found to decrease appetite when it activates NPY receptors in the brain. At least two biotech companies (Amylin and Nastech) have investigated using PYY directly as a drug to induce weight loss. So far this effort has had only mixed results.

Here's another report on the research discussed above: How we can stop stress from making us obese. And here's a blog post that raises some good questions about this research: Scientists Stressed About Weight Loss.

Apart from the effects of NPY, chronic stress can cause a variety of health problems besides weight gain, obesity, and their knock-on effects. Robert Sapolsky of Stanford has done copious research into the ill effects of chronic stress. He points out that the fight-or-flight response of animals in the wild, which is activated during periods of acute danger (predators), and is adaptive in those circumstances, can turn harmful when stress is chronic, as happens frequently with primates such as humans:

Why Do Humans And Primates Get More Stress-related Diseases Than Other Animals?
Why do humans and their primate cousins get more stress-related diseases than any other member of the animal kingdom? The answer, says Stanford University neuroscientist Robert Sapolsky, is that people, apes and monkeys are highly intelligent, social creatures with far too much spare time on their hands.

"Primates are super smart and organized just enough to devote their free time to being miserable to each other and stressing each other out," he said. "But if you get chronically, psychosocially stressed, you're going to compromise your health. So, essentially, we've evolved to be smart enough to make ourselves sick."

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Readings, 29 July 2007

Sunday, July 29, 2007

Comments, if any, apply to the article that precedes them.

Sea Anemone Genome Provides New View Of Our Multi-celled Ancestors
The first analysis of the genome of the sea anemone shows it to be nearly as complex as the human genome, providing major insights into the common ancestor of not only humans and sea anemones, but of nearly all multi-celled animals.

A new type of spin valve that uses graphene
“Some people think that graphene, a form of carbon, is the material of the future,” Allen Goldman tells PhysOrg.com. “It’s of high scientific interest because of its unusual electronic properties.”

Secrets of a Heavyweight
A dozen years after it first appeared on the world stage, the top quark is still one of the hottest topics in particle physics. Why is it so much heavier than any other particle? And what can it tell us about the origin of mass and other quantum mysteries? Here’s a look at the top’s quirky nature, its fevered past and its promising future.

[Comment: This is not a bad overview of top quarks – if you can stand the odd formatting and silly cartoons in here. -ed.]

Finding Clues to Aging in the Fraying Tips of Chromosomes
When Time magazine named Elizabeth H. Blackburn, a cell biologist, one of this year’s “100 Most Influential People in the World,” it listed her age as 44.

“Don’t think I’m going to ask for a correction on that one,” Dr. Blackburn, 58, a biochemistry professor at the University of California, San Francisco, said in a recent visit to New York City. “If they want to turn back the clock, that’s lovely.”

Dr. Blackburn, a winner of the 2006 Albert Lasker Award for Basic Medical Research, studies aging and biochemical changes in cells that are related to the diseases of old age.

Whatever Dr. Blackburn’s own chronologic age, the buzz in scientific circles is that she is likely to be the next woman awarded the Nobel Prize in Medicine.

[Comment: Here's an example of much better than average New York Times science writing. It's structured as an interview, so the expert's insights don't get obscured by the reporter's paraphrasing. The interviewee has eye-opening things to say about telomeres, telomerase, and the significant harmful effects of psychological stress. As well as the inner workings and unethical practices of the government's phony "Council on Bioethics" with regard to embryonic stem cells. -ed.]

Vitamin C Is Not Much Help Fighting Colds, Study Shows
A large review of placebo-controlled trials of vitamin C for cold prevention and treatment has concluded that it is largely ineffective.

In 30 trials involving 11,350 participants who took at least 200 milligrams of vitamin C a day, researchers found no reduction in the incidence of common colds. Vitamin C did reduce the duration and severity of cold symptoms slightly, but the effect was so small as to be clinically insignificant.

[Comment: True believers in the value of vitamin C advocate daily doses of a few grams, not fractions of a gram. It's hard to tell from this article whether the review in question focused at all on the possible efficacy of large doses. And the reporter fails to raise that important issue. The ambiguity regarding dose size and lack of objectivity that can be seen in the press release leaves one still wondering about the real truth of the matter. -ed.]

At Fermilab, the Race Is on for the ‘God Particle’
For physicists, this is a summer of rumors, hope and hype as rival collaborations race to capture the legendary particle known as the Higgs boson.

[Comment: Here's another specimen of overwritten New York Times science journalism, heavily laden with gooey, sticky "human interest" and pop sociology of science – on top of that fatuous theistic epithet in the headline. There's interesting information on the high-energy physics culture in here, but you may need an extra shot of insulin after reading it. -ed.]

Stellar fireworks in galaxy NGC 4449

Thursday, July 26, 2007

Stellar fireworks in galaxy NGC 4449 (7/3/07)
Hundreds of thousands of vibrant blue and red stars are visible in this new image of galaxy NGC 4449 taken by the NASA/ESA Hubble Space Telescope's Advanced Camera for Surveys (ACS). Hot bluish white clusters of massive stars are scattered throughout the galaxy, interspersed with numerous dustier reddish regions of current star formation. Massive dark clouds of gas and dust are silhouetted against the bright starlit background.

NGC 4449 – Click for 1280×1024 image

Metathoughts about brains

Tuesday, July 24, 2007

It occurs to me that there is an interesting connection between the two posts tonight. (This and this.) The first touches on the evolutionary origins of brains as sensory organs. The second (or rather, some references it contains) shows how sensory functions of human brains are still expanding – into huge space telescopes and even huger devices to sense gravitational waves.

Worth thinking about?

Origins of brains as sensory organs

Recently (well, not too long ago) I posted (here) a bit about how elements of the modern nervous system of vertebrates can be traced back to some of the most primitive animals – sea sponges.

Now it transpires that the origins of specific brain subsystems can also be found in invertebrates. In this case, the subsystem is the hypothalamus. One of the interesting things about the hypothalamus is that it is not only an important part of the central nervous system, but also part of the endocrine system. As such, it causes production of a number of important hormones itself, such as melatonin, oxytocin, and corticotropin-releasing hormone. It is further tied into the endocrine system via its direct connection to the nearby pituitary gland. Some of these hormones appear to have invertebrate origins the same as the hypothalamus itself:

Modern Brains Have An Ancient Core
Hormones control growth, metabolism, reproduction and many other important biological processes. In humans, and all other vertebrates, the chemical signals are produced by specialised brain centres such as the hypothalamus and secreted into the blood stream that distributes them around the body.

Researchers from the European Molecular Biology Laboratory [EMBL] now reveal that the hypothalamus and its hormones are not purely vertebrate inventions, but have their evolutionary roots in marine, worm-like ancestors. In this week's issue of the journal Cell they report that hormone-secreting brain centres are much older than expected and likely evolved from multifunctional cells of the last common ancestor of vertebrates, flies and worms.

The invertebrate in question here is the marine ragworm Platynereis dumerilii. And if the foregoing findings weren't interesting enough, it seems that not only vertebrates share a common ancestor (Urbilateria) with P. dumerilii, but so too do insects and other worms. Furthermore, P. dumerilii has two types of light-sensing cells – one type of which is found in insects, and the other is found in vertebrates.

Marine Worm Has Insectile and Vertebrate 'Eyes'
Scientists today believe that the eye could evolve from a single light-sensing cell. Scientists disagree over whether it evolved just once, or many times.

It turns out that Nature is both creative and generous with her gifts. Recent research has shown that the tiny marine worm Platynereis dumerilii has two types of light-sensing cells. The eyes of the worm have rhabdomeric photoreceptors, a compound lens formation that is seen almost exclusively in insect eyes. Rhabdomeric photoreceptors are covered in little finger-like protrusions. In its brain, however, it has a different kind of light-sensing cells - ciliary cells that are seen in vertebrate animals. Ciliary cells have hair-like cilia that extend outward and branch out like tiny umbrellas. Two different ways of sensing light in a single organism!

In light of this circumstance, the following, from the first-mentioned research announcement, is especially interesting:
Both of the cell types studied in Platynereis and fish are multifunctional: they secrete hormones and at the same time have sensory properties. The vasotocin-secreting cells contain a light-sensitive pigment, while RF-amide appears to be secreted in response to certain chemicals. The EMBL scientists now assume that such multifunctional sensory neurons are among the most ancient neuron types. Their role was likely to directly convey sensory cues from the ancient marine environment to changes in the animal's body. Over time these autonomous cells might have clustered together and specialised forming complex brain centres like the vertebrate hypothalamus.

"These findings revolutionise the way we see the brain," says Tessmar-Raible. "So far we have always understood it as a processing unit, a bit like a computer that integrates and interprets incoming sensory information. Now we know that the brain is itself a sensory organ and has been so since very ancient times."

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Readings, 23 July 2007

Articles I've come across that may be worth a look.

Thinking Big about Space Telescopes
NASA's next moon rocket is still on the drawing board, but already scientists are dreaming up big new things to do with it.

Astrophysicists draw up wish list
Astroparticle physicists in Europe have identified six key challenges that they face and the new facilities that they need to meet their research aims. Their plans for the next ten years have been outlined in The Astroparticle Physics Roadmap Phase 1 published by ApPEC and ASPERA, which are consortia of national agencies that pay for astroparticle physics research in Europe.

Sounding out the Big Bang
Gravitational waves offer a unique way of studying inflation and other fundamental processes of the very early universe, explains Craig J Hogan, and may even connect string theory with the world of experiment.

The last article here is an absolute must-read if you're curious about the science of "evo devo".

From a Few Genes, Life’s Myriad Shapes
Since its humble beginnings as a single cell, life has evolved into a spectacular array of shapes and sizes, from tiny fleas to towering Tyrannosaurus rex, from slow-soaring vultures to fast-swimming swordfish, and from modest ferns to alluring orchids. But just how such diversity of form could arise out of evolution’s mess of random genetic mutations — how a functional wing could sprout where none had grown before, or how flowers could blossom in what had been a flowerless world — has remained one of the most fascinating and intractable questions in evolutionary biology.

Health benefits of omega-3 fatty acids

Saturday, July 21, 2007

Omega-3 fatty acids are now getting credit for health benefits in a surprising range of disease conditions.

Just to review a little, fats and fatty acids are said to be saturated if they have the maximum possible number of hydrogen atoms attached. In particular, a fatty acid is unsaturated if it has at least one double C-C bond on its main hydrocarbon chain. (An atom of hydrogen could potentially be attached there.) It is polyunsaturated if it has at least two. By definition, an omega-3 fatty acid is polyunsaturated, and in addition one of its double bonds occurs as close as possible to the end of the main chain that is opposite the carboxyl (COOH) group required in a fatty acid.

Curiously enough, this simple chemical property – rather than any more complicated chemical configuration – appears to be sufficient to confer a variety of health benefits on omega-3 fatty acids.

Perhaps the best-known benefit, for which there is evidence in studies of particular (not all) omega-3 fatty acids, is related to coronary heart disease (e. g. atherosclerosis or "hardening of the arteries"). The omega-3 fatty acids most frequently involved are eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA).

But recent research has encompassed many other disease conditions, for example, abnormal blood vessel growth that can cause blindness, such as that which may occur in retinopathy of premature infants, diabetic retinopathy, and "wet" age-related macular degeneration.

Omega-3 fatty acids protect eyes against retinopathy, study finds
The researchers studied the effect of the omega-3 fatty acids EPA and DHA, derived from fish, and the omega-6 fatty acid arachidonic acid on the loss of blood vessels, the re-growth of healthy vessels, and the growth of destructive abnormal vessels in a mouse model of oxygen-induced retinopathy. The retinopathy in the mouse shares many characteristics with retinopathy of prematurity (ROP) in humans. ROP is a disease of the eyes of prematurely born infants in which the retinal blood vessels increase in number and branch excessively, sometimes leading to bleeding or scarring. Infants who progress to a severe form of ROP are in danger of becoming permanently blind. There are also aspects of the disease process that may apply to diabetic retinopathy, a disease in which blood vessels swell and leak fluid or grow abnormally on the surface of the retina, and age-related macular degeneration (AMD), a disease of the macula, the part of the retina responsible for central vision, and a leading cause of vision loss in Americans 60 years of age and older.

Typical Western diets are lacking in omega-3 fatty acids, which are found mainly in shellfish and oily fish (e. g. salmon, sardines), and instead have a much higher percentage of omega-6 fatty acids. (In an omega-6 fatty acid, the only difference is that the first C-C double bond occurs farther from the end of the hydrocarbon chain that is opposite the carboxyl group. See these Wikipedia articles for more details: essential fatty acids, essential fatty acid interactions.) It turns out, oddly enough, that omega-6 fatty acids can have deleterious effects, just the opposite of omega-3 effects.
The researchers found that increasing omega-3 fatty acids and decreasing omega-6 fatty acids in the diet reduced the area of vessel loss that ultimately causes the growth of the abnormal vessels and blindness. Omega-6 fatty acid contributes to the growth of abnormal blood vessels in the retina.

To further test the apparent beneficial effect of omega-3 fatty acids, the researchers studied mice fed a diet modeled after a traditional Japanese diet (more omega-3 than omega-6 fatty acids) and mice fed a diet modeled after a traditional Western diet (lower amounts of omega-3 fatty acids). In addition, they studied mice genetically altered with a gene which mammals normally lack that converts omega-6 into omega-3 fatty acids. They found that the mice with higher amounts of omega-3 had a nearly 50 percent decrease in retinopathy.

Most importantly, this research identified a likely mechanism of action by which omega-3 fatty acids confer their benefits. The mechanism involves suppression of inflammation, especially involving the inflammatory cytokine TNF-α. In particular, this would apply to atherosclerosis, in which inflammation is generally regarded as a significant problem. Such anti-inflammatory properties, if indeed present, could account for the benefits of omega-3 fatty acids in other circumstances also. Another report on the same research describes this:

Can Blindness Be Prevented Through Diet?
Omega-3 fatty acids like DHA and EPA are thought to dampen inflammation in the body. ...

The researchers demonstrated that the omega-3-based diet suppressed production of TNF-alpha, reducing the inflammatory response in the retina, whereas the omega-6-based diet increased TNF-alpha production. The retinas of omega-3-fed mice also had increased production of the anti-inflammatory compounds neuroprotectinD1, resolvinD1 and resolvinE1. These compounds, derived from omega-3 fatty acids, also potently protected against pathological vessel growth, and they were not detected in the retinas of mice fed the omega-6 diet.

Cancer is a rather more controversial case in connection with possible health benefits of omega-3 fatty acids. Many epidemiological studies have been done to try to identify cancer-protective effects of omega-3 in the diet, with varying results. Meta-analysis of such studies does not identify a conclusive connection. However, such studies are hampered by uncertainties about the actual diets consumed by participants. Additionally, a lot may depend on individual genetic factors. In animal studies it is possible to be much more quantitatively precise. For instance, we have this:

Omega-3 Fatty Acids May Help Slow Prostate Cancer Growth
The mice were fed either a diet high in omega-3 (ratio of omega-6 to omega-3 was 1:1) a diet low in omega 3 (ratio omega-6 to omega-3 was 20:1), or a diet high in omega-6 (ratio of omega-6 to omega-3 was 40:1). The scientists compared survival rates and weighed the animals' prostates to measure tumor progression.

Mice with the tumor suppressor gene remained free of tumors and had 100 percent survival, regardless of diet. In mice with the gene defect, survival was 60 percent in animals on the high omega-3 diet, 10 percent in those on the low omega-3 diet and 0 percent in those on the high omega-6 diet.

"This suggests that if you have good genes, it may not matter too much what you eat," said [senior researcher Yong Q.] Chen, a professor of cancer biology. "But if you have a gene that makes you susceptible to prostate cancer, your diet can tip the balance. Our data demonstrate the importance of gene-diet interactions, and that genetic cancer risk can be modified favorable by omega-3 PUFA."

In a rather different direction, there has been a lot of suspicion, and some epidemiologial and experimental evidence, that omega-3 fatty acids and higher omega-3:omega-6 ratios have beneficial effects in connection with psychological and mood disorders. So it makes sense that omega-3 could be useful with the symptoms of agitation and depression associated with Alzheimer's disease. It turns out that benefits may be significantly dependent on genetic factors related to the disease:

Omega-3 Supplements Can Help With Alzheimer's Symptoms, Study Suggests
Omega-3 supplements can, in certain cases, help combat the depression and agitation symptoms associated with Alzheimer's disease, according to a clinical study conducted at the Swedish medical university Karolinska Institutet.

A number of epidemiological studies have shown that eating fatty fish provides a certain degree of protection against Alzheimer's and other dementia diseases--an effect often thought attributable to the omega-3 fatty acids it contains. Some studies also suggest that omega-3 can have a therapeutic effect on some psychiatric conditions.

The results were not straightforward, to put it mildly. There is a well-known susceptibility gene for Alzheimer's, APOE4. Carriers of the gene experienced benefits for agitation symptoms, while non-carriers had benefits for depression symptoms!
There was no observable difference in therapeutic effect between the patients receiving the omega-3 and the placebo group. However, when the researchers took into account which of the patients carried the susceptibility gene APOE4 and which did not, an appreciable difference appeared. Carriers of the gene who had received active treatment responded positively to the omega-3 as regards agitation symptoms, while non-bearers of the gene showed an improvement in depressive symptoms.

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Philosophia Naturalis #12 has been published

Friday, July 20, 2007

And as previously announced, it's at a geocentric view. (And it even appeared on time this month, unlike this notice.) Definitely worth your time to read a bit.

Thanks to mollishka for doing and hosting this month's edition.


Tuesday, July 17, 2007

There's been a bit of news recently about axions.

But first, what is an axion, and why should anyone care? Don't we have enough oddball particles already? Perhaps we do, but regardless of that, the properties axions are hypothesized to possess would be a good fit for what is needed in a particle that could make up at least some dark matter.

Specifically, the theory behind axions predicts that they would be rather light, but not massless – between 10-6 and 10-2 eV/c2. For comparison, the mass of an electron is about 510,999 eV/c2. On the other hand, neutrinos (all three types) are known to have mass, and though this mass isn't well determined, axions would be in the same range.

Just as axions interact very weakly with gravity, they should interact very weakly, if at all, with the weak and strong nuclear forces. In particular, axions should have no electric charge. These properties make them good dark matter candidates, unlike neutrinos, which do feel the weak force.

On the surface, the most recent news, concerning the failure of an experimental attempt to detect axions, appears to be discouraging. But the silver lining is that if the experiment had actually detected axions, it would imply that they couple too strongly to photons to be a dark matter candidate. For that reason, this failure has been greeted with a bit of relief.

You see, one other expected property of axions is that in the presence of a strong magnetic field, axions could transform into photons, or vice versa. This makes it possible to design certain experiments for detecting axions, as we shall see.

Theoretically, the reason axions were predicted to exist in the first place has to do with breaking of charge-parity (CP) symmetry by the strong nuclear force. Or rather, the apparent failure of CP symmetry breaking by the strong force.

CP symmetry breaking was first discovered in 1964 in connection with the weak force. Even there, the effect is small, but by now it has been verified and measured repeatedly. Quantum chromodynamics (QCD) is the quantum field theory of the strong force, and it is similar enough to the theory of the weak force that there is no apparent reason CP symmetry breaking isn't observed with the strong force.

There is a parameter in the equations called θ which describes the amount of symmetry breaking. To accord with experimental results, θ must be fine-tuned to be extremely close to 0, even though it could have any value from 0 to 2π. Physicists do not like such fine tuning, and so they have given the name "strong CP problem" to the lack of CP breaking by the strong force, or alternatively the smallness of θ.

The solution to this problem that has been most popular with physicists is based on what is called the Peccei-Quinn mechanism, after Roberto Peccei and Helen Quinn, who were both at Stanford in 1977 when they came up with theory. (Trivia note: I sat in on a quantum field theory course given by Peccei in 1974. As I was in mathematics, it didn't make a whole lot of sense to me then, what with all the Feynman integrals and such flying around, oblivious to their lack of rigorous mathematical definition. I also recall the class meeting in November 1974 when the discovery of the J/Psi particle was announced. I didn't understand what all the exceitement was about, either. Future astronaut Sally Ride, then a physics grad student, was also in the class.)

Anyhow, the Peccei-Quinn proposal was to make this parameter θ into a quantum field (meaning it could have different values at different points). Along with this field, there should be a new global symmetry (Peccei-Quinn symmetry) that, however, is spontaneously broken. As Frank Wilczek and Steven Weinberg then showed, this implies the existence of a particle – which Wilczek called the axion, because it "cleaned up" the theory. (Axion was the name of a popular brand of laundry soap.) They also showed this would be a satisfactory solution to the strong CP problem.

It would be even more satisfactory if experiments could actually detect axions. But in the 30 years since then, this has not happened.

That basically brings us to the latest news about axions. Because axions and photons can turn into each other, it turns out that if a beam of polarized light is passed through a strong magnetic field a small rotation in the direction of polarization should occur, due to interaction of the photons with the magnetic field, creating real or virtual axions.

The PVLAS laboratory in Italy has been conducting such an experiment for several years. For awhile the reasearchers thought they has obtained positive results. Sadly, no. Just a couple weeks ago the researches reported their earlier results couldn't be reproduced:

Axions ruled out by PVLAS

The existence of a hypothetical particle called the axion has been put into further doubt now that the team that first claimed its discovery has failed to reproduce their results. Physicists working on the PVLAS experiment in Italy say that the tiny rotation in the polarization of laser light that they reported last year does not support the existence of axions, but rather is an artefact related to how the experiment had been performed.

But the silver lining is:
The latest news from Italy should come as a relief to physicists who believe that axions could make up dark matter. This is because the PVLAS axion appeared to couple too strongly to light to be a suitable candidate for dark matter.


Gene activation by CREB

Thursday, July 12, 2007

Here's more illustration, if any were needed, of the point that gene expression is a much more complex process than has sometimes been supposed. We recall that transcription factors are proteins that are necessary for a gene to be expressed, and they do their job by binding to a section of DNA (called a promoter) near the gene. To make matters more interesting, it is usually necessary to have other proteins involved, and some bind to the transcription factor rather to the promoter. Such proteins are called cofactors. If the effect is to increase gene expression, the protein is called a coactivator. You may recall that a coactivator played an important role in this post about metering gene expression.

As it happens, we mentioned an important type of transcription factor, called cAMP responsive element binding proteins (CREB) in our recent post on histone deacetylase enzymes. The general situation is that a CREB is part of a cell-signaling pathway, in which a signal arrives at a cell surface, activating some cell surface receptor. As a result, a secondary signal is generated within the cell, consisting of a cAMP molecule, which in turn activates a protein kinase, which finally activates a CREB protein. This last may then act as a transcription factor, causing a particular gene to be expressed, with the resulting protein being the cell's response to receipt of the original signal.

The interesting thing is that, according to the following research, the target gene "chooses" which cofactors are needed along with the CREB to initiate gene transcription. (Is that really surprising? I don't know. It seems one might have guessed that each gene promoter requires something slightly different to allow transcription, so that transcription depends not only on the received signal, but also on other varying conditions.)

Genes Play An Unexpected Role In Their Own Activation, Study Shows

Investigators at St. Jude Children's Research Hospital have discovered how a single molecular "on switch" triggers gene activity that might cause effects ranging from learning and memory capabilities to glucose production in the liver.

The "on switch," a protein called CREB, is a transcription factor--a molecule that binds to a section of DNA near a gene and triggers that gene to make the specific protein for which it codes. CREB activates genes in response to a molecule called cAMP, which acts as a messenger for a variety of stimuli including hormones and nerve-signaling molecules called neurotransmitters.

The St. Jude team showed that each gene that responds to CREB chooses which co-factors, or helper molecules, CREB uses to activate that gene. This finding adds an important piece to the puzzle of how cells use CREB to activate specific genes in response to cAMP signals.

One of the report authors, Paul Brindle, offers this analogy:
"CREB is like a plumber who turns on the water flow in a pipe system by using a certain tool," Brindle said. "What we discovered is that the CREB 'plumber' requires different tools to turn on different genes; and that each gene determines which set of co-factor tools from CREB's toolbox it will respond to."

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Why stem cells are stem cells

This seems like a pretty fundamental finding regarding what makes a stem cell a stem cell:

Five Genetic Themes Key To Keeping Stem Cells In A Primitive, Flexible State Have Been Identified
For more than 25 years, stem cells have been defined based on what they can become: more of themselves, as well as multiple different specialized cell types. But as genetic techniques have become increasingly powerful, many scientists have sought a more molecular definition of stem cells, based on the genes they express.

Now, a team of Canadian scientists has identified 1,155 genes under the control of a gene called Oct4 considered to be the master regulator of the stem cell state. A comprehensive molecular definition of stem cells is emerging: according to this research, stem cells are cells that keep their DNA packaged in a flexible format, keep cell division tightly controlled, prevent signals that might trigger death, repair DNA very effectively, and reinforce all of these characteristics by tightly controlling how molecules can move within the nucleus.


Philosophia Naturalis #12 call for submissions

Mollishka at a geocentric view will be hosting the next edition of the carnival on Thursday, July 19. The announcement is here.

Submissions should be made by Tuesday night, July 17. An email address for submissions is in the announcement, or you can use this handy form. The editor's area of expertise is astronomy, so I'm sure submissions in that area will be welcome, but so will those in other traditional physical sciences (physics, math, earth science, chemistry, etc.)

Let's make this another great collection of physical science writing.

Disease genes

Tuesday, July 10, 2007

This is old news (over a month), and it was widely reported in the general media, so I'm sure most readers are aware of it. But it seems important enough to note here, just for the record. It might be considered one of the most important science stories of the year.

Largest Ever Study Of Genetics Of Common Diseases Published
The Wellcome Trust Case Control Consortium, the largest ever study of the genetics behind common diseases such as diabetes, rheumatoid arthritis and coronary heart disease, published its results in the journals Nature and Nature Genetics.

The £9 million study is one of the UK's largest and most successful academic collaborations to date. It has examined DNA samples from 17,000 people across the UK, bringing together 50 leading research groups and 200 scientists in the field of human genetics from dozens of UK institutions. Over two years, they have analysed almost 10 billion pieces of genetic information.

Information about a couple of autoimmune diseases figured prominently in the results.
Amongst the most significant new findings are four chromosome regions containing genes that can predispose to type 1 diabetes and three new genes for Crohn's disease (a type of inflammatory bowel disease). For the first time, the researchers have found a gene linking these two autoimmune diseases, known as PTPN2.

The study has also confirmed the importance of a process known as autophagy in the development of Crohn's disease. Autophagy, or "self eating", is responsible for clearing unwanted material, such as bacteria, from within cells. The may be key to the interaction of gut bacteria in health and in inflammatory bowel disease and could have clinical significance in the future.

"The link between type 1 diabetes and Crohn's disease is one of the most exciting findings to come out of the Consortium," says Professor John Todd from the University of Cambridge, who led the study into type 1 diabetes. "It is a promising avenue for us to understand how the two diseases occur. The pathways that lead to Crohn's disease are increasingly well understood and we hope that progress in treating Crohn's disease may give us clues on how to treat type 1 diabetes in the future."

There were also findings about genetic factors in obesity, type 2 diabetes, and heart disease. In fact, seven major disease in all:
These are bipolar disorder, Crohn's disease, coronary heart disease, hypertension, rheumatoid arthritis and type 1 and type 2 diabetes.

Interestingly, rheumatoid arthritis is also an autoimmune disease. And the immune system (especially in regard to inflammation) probably plays some role in other ailments on this list.

Most readers here probably understand that very seldom is a single gene ever the sole "cause" of a particular disease. Instead, what has been found, in this study and in others, is a number of variants (called alleles) of a variety of genes, where one of more of the variants, if present in an individual, increases the person's risk of eventually developing the disease – conditioned on the presence of other genetic variations, environmental conditions, and so forth. As another account explains:

Sick Genes
[G]enes, although potent predictors, are not always the sole cause of particular diseases. For instance, environmental factors, lifestyle (diet, exercise, etcetera) and exposure to infections can all play roles in determining whether an individual will develop heart disease, for example. "It's about hundreds of genes in your genome contributing a threshold of genetic susceptibility," Todd says. "It's not about one gene."

Nevertheless, on average, having one copy of some of the newly identified genes raises a person's chances of developing one of the seven studied diseases by 20 to 40 percent, and those with two copies face nearly double that risk, researchers say. "What hasn't been clear is exactly which bits of the genome have an effect and which variants make people more [or less] likely to get a disease," Donnelly notes.

Additional news reports: here, here, here, here.

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Histone deacetylase enzymes

Monday, July 9, 2007

You don't often hear histone deacetylase (HDAC) enzymes being discussed in ordinary conversation at cocktail parties or around the water cooler – unless perchance you stumble into a conversation among biomedical researchers.

But that might change a bit sometime in the not too distant future. HDAC and HDAC inhibitors are increasingly one of the "hot" topics in cancer research, and their importannce is now leaking out into a variety of disparate areas of biomedicine. There are even connections with other trendy topics, such as the SIR2 "longevity gene" and the NF-κB transcription factors.

Perhaps I should back up a moment and say a few words about histones and histone deacetylases. As you know, DNA generally does not float around all by itself inside a cell. With about 3 billion base pairs, human DNA, simply in order to fit into a cell in an orderly way, needs to be kept most of the time in a very compact form within the 23 chromosome pairs. The material making up chromosomes is called chromatin, which is made up of protein complexes called nucleosomes, around which the DNA is wound. Each nucleosome in turn is made up mostly of a core containing 8 histone proteins of several different types.

This arrangement has important implications for gene expression, because genes that occur in a portion of DNA that is wrapped tightly around a nucleosome are not readily available for translation into messenger RNA, which determines when and how proteins corresponding to the gene can be constructed. However, when an acetyl group is attached to one or more histones of a nucleosome, the DNA becomes less tightly bound, so that its genes can be more easily expressed.

Conversely, removing acetyl groups that may be attached to histones of the nucleosome largely inhibits access to the genes, effectively "silencing" them. A histone deacetylase is an enzyme that removes acetyl groups, so it is a mechanism for silencing groups of genes. About 11 HDACs (depending on how one counts) are known in higher eukaryotic cells.

This gene silencing is anything but a trivial function. For example, the proteins Sirtuin and Sir2 (Sirt1 in mammals), variations of which are found in most eukaryotic cells and are known to be involved with aging, are HDACs. On the other hand, cancer tumors frequently take advantage of HDACs to silence genes that would otherwise promote cancer cell death.

Because of the role of HDACs in cancer, an inhibitor of an HDAC is a potential anti-cancer drug. As we will see, there are a number of these now in clinical trials to fight various cancers – and one has even been approved by the FDA for use (Vorinostat, also known as suberoylanilide hydroxamic acid (SAHA)).

For a great source of technical information on HDACs, especially in relation to cancer, check here.

Following are some research announcements pertaining to HDACs. They are mostly recent, and have been appearing at an increasing rate. Note how some of the most recent ones are in areas well outside of oncology.

Future Therapies For Stroke May Block Cell Death (6/14/07)
Substantial neurological damage occurs in strokes and neurodegenerative diseases like ALS, Parkinson's, and Huntington's. Researchers suspect that there are neuroprotective proteins whose expression could be increased to limit cell death if an inhibitor for the appropriate HDAC can be found.

At Penn, 'tantalizing' finds in cell research (6/14/07)
There are various neurodegenerative diseases which involve damaged or misfolded proteins that are toxic to cells. There is a mechanism called autophagy that is capable of disposing of such proteins, but it does not work fast enough in the presence of disease. Researchers have found that HDAC6 can facilitate autophagy and mitigate disease in a fruit fly model.

Gene Switched Off In Cancer Can Be Turned On, Researchers Discover (6/12/07)
A gene whose protein controls cell growth, called Brahma or BRM, is silent but not missing or mutated in some cancer cells. It is turned off in about 15 percent of tumors studied, including cells from lung, esophageal, ovarian, bladder, colon and breast cancers. HDAC inhibitors were found that could undo the silencing of the gene.

Cancer Drug Enhances Long-term Memory (6/6/07)
In a study with mice, researchers have shown that HDAC inhibitors together with a protein called CBP can enhance memory and actually strengthen neural connections in the hippocampus. CBP is known to relax chromatin, making gene expression easier in affected portions of DNA. Presumably the HDAC inhibitors prevent undoing the effect of CBP. Use of HDAC inhibitors alone did not have an effect on memory. If this effect exists in humans, CBP and HDAC inhibitors could be a therapy for people with Alzheimer's and Huntington's diseases and Rubenstein-Taybi syndrome.

Vorinostat Shows Anti-cancer Activity In Recurrent Gliomas (6/5/07)
Vorinostat is the first FDA approved oral anti-cancer agent that is an HDAC inhibitor. It has been shown to be effective as a treatment for cutaneous T cell lymphoma. This study indicates it also shows activity in patients with recurrent glioblastoma multiforme.

Eat Your Broccoli: Study Finds Strong Anti-Cancer Properties In Cruciferous Veggies (5/18/07)
Cruciferous vegetables such as broccoli, bok choy, and brussels sprouts contain significant amounts of sulforaphane, which has noteworthy anti-cancer properties. This research suggests that cruciferous vegetables have HDAC inhibiting effects, which might explain their anti-cancer properties.

Healthy Muscles: Scientists Identify Pathway That Promotes Muscle Cell Survival In Mice (5/1/07)
Mice genetically engineered with a defective protein called cAMP responsive element binding protein (CREB) have poorly developed muscles. This appears to be related to lack of inhibition of a specific HDAC enzyme when CREB is defective. Investigation revealed that production of an enzyme called salt-inducible kinase-1 (SIK1) is also inhibited in the presence of defective CREB. SIK1 was found to phosphorylate the HDAC protein, which inhibits its histone deacetylation capability. Further experimentation showed that raised SIK1 levels or use of other inhibitors of the HDAC enzyme also restored muscle cell health in the mice with defective CREB. The findings may lead to treatments for diseases that affect cell survival, such as muscular dystrophy, neurodegenerative diseases, and congestive heart failure.

Novel Drug Shows Potential For Treating Leukemia (4/21/07)
HDAC inhibitors, when used in combination with an experimental proteasome inhibitor drug, NPI-0052, were more effective at inhibiting the main enzymatic activity of the proteasome than NPI-0052 alone. Either alone or in combination NPI-0052 was much more effective than bortezomib (marketed as Velcade), the only FDA-approved proteasome inhibitor. Proteasomes clean out mutated or damaged proteins within cells, but in cancer cells this allows unwanted cell growth and reproduction. Proteasome inhibitors block this process, resulting in apoptosis of the malignant cells. Although bortezomib is effective for treating multiple myeloma and mantle cell lymphoma, it is ineffective by itself against leukemia, so NPI-0052 may be a good alternative.

Scientists Induce Cell Death In Leukemia (4/17/07)
The proteasome inhibitor bortezomib when used in combination with either of two HDAC inhibitors (romidepsin and belinostat) was shown in preclinical tests to be very lethal to cultures of human chronic lymphocytic leukemia cells. Other preclinical and clinical data suggest similar synergistic effects of bortezomib in additional cancer cell types.

Treatment Extends Survival In Mouse Model Of Spinal Muscular Atrophy (2/23/07)
Spinal muscular atrophy (SMA) is the most common severe hereditary neurological disease of childhood and is usually fatal. SMA is caused by mutations in a gene called SMN1. A related gene called SMN2 can sometimes produce the SMN protein, but in very small amounts. A drug called trichostatin A (TSA) is a potent HDAC inhibitor that is an antifungal antibiotic and has been found capable of increasing SMN protein production from the SMN2 gene in a mouse model and in cells from SMA patients. Improved survival was observed in the mouse model of SMA.

Two Drugs May Stabilize Plaques In Atherosclerosis (11/15/06)
An anti-fungal drug and an anti-cancer drug – TSA and SAHA (see references elsewhere in this report) – have been reported to decrease cholesterol deposits in the walls of arteries. In this case, the drugs appear to have an anti-inflammatory mechanism. The two compounds decreased inflammatory proteins produced by macrophages taken from normal mice. Such inflammatory proteins can make atherosclerotic plaque unstable. After the macrophages were treated with either TSA or SAHA, dramatic decreases were measured in LDL and total cholesterol in the macrophages. In addition, the drugs prevented macrophages from turning into foam cells inside arterial walls,

Researchers Make Advances In Attacking Leukemia Cells (10/21/05)
This somewhat older research demonstrated that in leukemia cells, HDAC inhibitors also induce changes in a master regulatory protein known as NF-κB, which is involved in regulation of inflammation, cell survival and many other functions. It was found that NF-κB inhibitors dramatically increased the lethality of HDAC inhibitors in various leukemia cell types. Such inhibitors are the subject of great interest as potential anti-inflammatory agents for use in various disorders, such as arthritis and inflammatory bowel disease. The research suggests they may also be valuable in enhancing the antileukemic efficacy of HDAC inhibitors, which have already shown antileukemic activity on their own.

MIT Researchers Uncover New Information About Anti-Aging Gene (2/18/00)
This is old and now well-known research by Leonard Guarente and associates, showing that an anti-aging gene, called Silent Information Regulator (SIR2), is an enzyme – specifically an HDAC enzyme. As such, SIR2 can silence genes in whole sections of a genome. As cells age, problems such as genome instability and inappropriate gene expression surface as genes that had always been turned off sometimes get turned on. SIR2 may forestall such age-related problems, which can lead to cell death. The research team found that yeast cells with an extra copy of SIR2 live longer, while yeast cells without SIR2 have a shorter lifespan. The connection with metabolism (and hence caloric restriction) may stem from a co-enzyme, called nicotinamide adenine dinucleotide (NAD), that is related to metabolism and is required for SIR2 to be activated.

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News dump: inflammation

Thursday, July 5, 2007

I've already done one news dump on the subject of inflammation (here), and there's been a lot of interesting stuff since then. This is just the first installment of new stuff, in reverse chronological order.

Schizophrenia may be linked to inflammation: study (3/21/07)
Many patients with schizophrenia also have autoimmune diseases. Using a technique called whole genome association researchers have located a gene variant common to many schizophrenics. The variant is located close to genes that produce receptors for two cytokines, which are immune system signals whose production is a first step in causing inflammation. Although the result is intriguing, the evidence for a relation to inflammation is still circumstantial.

Why Aerobic Exercise Is Good For The Heart (3/21/07)
The biological mechanisms connecting exercise and cardiovascular health are not fully understood. This study shows how exercise decreases inflammation, which reduces the risk of atherosclerosis, which in turn causes most cases of heart disease. Blood samples were taken from experimental volunteers before and after aerobic exercise. The samples were stimulated with an infectious agent and then analyzed for levels of tumor necrosis factor (TNF), an initial step in the inflammatory cascade. Substantially lower levels of TNF were found after aerobic training

Inflammation May Play Role In Metastasis Of Prostate Cancer (3/19/07)
This research strongly suggests that inflammation associated with the progression of tumors plays a key role in the metastasis of prostate cancer. It appears that inflammation in the tumor may lead to production of a cytokine called RANK. This eventually results in turning down the expression of a gene called Maspin, which has well-established anti-metastatic activity in breast and prostate cancers.

Researchers Identify Molecular Basis Of Inflammatory Bowel Disease (3/15/07)
The category of inflammatory bowel diseases includes Crohn's disease and ulcerative colitis. A likely molecular basis for such diseases has been identified in a mouse model. It appears that there is an underproduction of the signaling molecule NF-kB, which helps cells cope with stress, in the intestinal epithelium. With insufficient NF-kB, epithelial cells are more likely to die, and as a result bacteria can penetrate the epithelium. This results in activation of the intestinal immune system, producing a strong immune response and inflammation. The inflammation leads to death of more epithelial cells due to lack of NF-kB, perpetuating the cycle.

Obstructive Sleep Apnea Patients Show Silent Brain Infarction Lesions (3/15/07)
Patients with sleep apnea often have high levels in their blood of inflammatory markers. Cardiovascular disease is commonly characterized by ongoing inflammatory responses that can enhance blood platelet activation and increase the risk of silent brain infarction (stroke). Treatment of patients with obstructive sleep apnea using devices to create positive airway pressure led to lower blood levels of C-reactive protein and levels of two markers of platelet activation, suggesting that the apnea played a causal role in inflammation.

Belly Fat May Drive Inflammatory Processes Associated With Disease (3/14/07)
This research strongly suggests that visceral fat present in significant amounts surrounding organs in the midsection of the body may be a major source of inflammatory molecules. The resulting inflammation is suspected to play an important role in diseases such as insulin resistance, hypertension, type 2 diabetes, and atherosclerosis, and possibly Alzheimer's, cancer, and general aging. The study was done by analyzing blood taken from the portal vein (which drains organs surrounded by visceral fat) during gastric bypass surgery. Elevated levels of the inflammatory cytokine IL-6 were found, along with higher levels of C-reactive protein.

C-Reactive Protein Liver Protein Induces Hypertension, Researchers Find (2/22/07)
Researchers claim to have found that C-reactive protein is not merely a marker of the risk of hypertension, it actually induces hypertension. Using a mouse model having an engineered gene for CRP that was regulated by another gene responsive to carbohydrate in the diet, the researchers determined that raising CRP levels increased blood pressure, while lowering CRP levels lowered blood pressure. (It has been known for some time that high CRP levels are correlated with risk of hypertension and atherosclerosis.) Further investigation showed that the experimental mice were highly sensitive to the blood pressure regulating protein angiotensin II, and this was due to alterations in key proteins in the vascular wall that are involved with angiotensin II. The mechanism involves a lack of nitric oxide in the artery wall, and a connection was found between nitric oxide and proteins responsible for angiotensin II activity. Remaining to be shown is whether the same mechanism operates in humans.

Inflammatory Genes Linked To Salt-sensitive Hypertension (12/30/06)
A team of researchers is investigating interrelations among genetic variations, stress, inflammation, and hypertension. One hypothesis is that sodium handling goes awry because of mutations in genes for the inflammation-related proteins IL-6, IL-6 receptor, cytokine signal transducer, and C-reactive protein. Stress is involved because of a suspicion that the connection between stress, inflammation and hypertension is the kidneys’ ability to release sodium. When stress activates the sympathetic nervous system, the body increases production of IL-6, which ultimately leads to production of other inflammatory factors such as CRP. Stress also prompts the body to hold onto sodium to help temporarily raise blood pressure in order to deal with the situation.

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Metering gene expression

Wednesday, July 4, 2007

As often noted, such as here, gene expression is really quite a complicated process.

Although the net result of DNA transcription is the production of messenger RNA under control of a complex enzyme called RNA polymerase, there's a lot more to it than that. In particular, transcription will usually not even begin unless certain proteins, called transcription factors, have attached themselves to a location on the DNA specific to each gene (called a promoter region). Such proteins are called activators because of the role they play.

To make matters even more complicated, sometimes additional proteins, called coactivators, must be attached to other activators instead of the DNA itself. Since transcription factor proteins are produced under control of other genes, this complex process makes it possible for certain genes to control or regulate the expression of other genes. Indeed, this is the normal state of affairs, and it works much like a computer program, in which the "final" result depends heavily on what else is going on at the same time or earlier.

It now appears that there is a further complication, and hence a further sort of control that is possible. In general it is not desirable that any particular gene remain "on" indefinitely, capable of directing the production of its corresponding protein without limits. Just as with a prescription medicine (which, in some sense, many of the proteins encoded by genes really are), it is often best to dispense only a certain limited quantity. This quantity may be sufficient for whatever its purpose is, and the system may need time to absorb it, with the possibility of producing more later if, and only if, the need still exists.

Research now indicates that in order to allow for such metered usage, some coactivators make it possible to keep a count of how often they are used, and they will automatically be destroyed after the maximum allowed number of uses is reached.

Clocking In And Out Of Gene Expression
"Inherent to the structure of these coactivators is a clock," he said. "But the clock needs to be set off." In studies of breast cancer cells, [senior investigator Dr. Bert] O'Malley and his colleagues showed how the clock works. Using steroid receptor coactivator-3 (SRC-3), they demonstrated that activation requires addition of a phosphate molecule to the protein at one spot and addition of an ubiquitin molecule at another point. Each time the message of the gene is transcribed into a protein, another ubiquitin molecule is chained on. Five ubiquitins in the chain and the protein is automatically destroyed.

"It's built-in self destruction," said O'Malley. "It prevents you from activating a potent factor in the cells that just keeps the clock running and the gene continuing to be expressed." In that scenario, the result could be cancer, too much growth or an abnormal function.

"It means there's a fixed length of time that the molecule can work. When it's activated, it's already preprogrammed to be destroyed. The clock's running and each time an ubiquitin is added, it is another tick of the clock." When the clock system fails, problems result.

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Finding protection from tumor growth in unexpected places

Monday, July 2, 2007

As just about anyone who takes even the simplest medications knows, almost everything has side-effects. Generally, there's no free lunch. The aspirin that reduces your fever and (maybe) makes your hangover a little less painful can also cause ulcers and stomach bleeding.

Among the many thousands of proteins, hormones, enzymes, and the like that are active naturally in your body at any one time, most presumably are there for a beneficial purpose. But not always. Some have a distinct Jekyll/Hyde quality about them.

Consider, in particular, the hormone known as angiotensin II. It is part of what is called the renin-angiotensin system, which helps regulate blood pressure. Overlooking a number of details, one of the key functions of angiotensin II is to quickly constrict blood vessels, to minimize blood loss in the event of serious injury. However, because it raises blood pressure, the body needs for it not to be around most of the time, to avoid dangerous hypertension.

The way the body handles this is by producing a slightly different hormone instead, angiotensin I, which can be quickly converted, when required, into angiotensin II by means of an enzyme called simply angiotensin-converting enzyme (ACE). It's ACE we're really here to talk about in this note, because it appears to have several other functions besides the one it's named for. Ironically, one of the strategies for treating hypertension is to inhibit ACE, because of the need to keep blood pressure under control. Yet some of its side effects, unrelated to blood pressure, seem beneficial.

Finding Protection From Tumor Growth In Unexpected Places
Researchers have discovered that an enzyme commonly involved in regulating blood pressure also provides protection from tumor growth when strongly expressed in immune cells.

ACE, in fact, is involved in a surprising number of other processes in addition to restraining tumor gowth via its immune system activity.
Angiotensin-converting enzyme (ACE) plays a direct role in controlling blood pressure and is a common therapeutic target in hypertension. However, it also plays roles in such diverse processes as fertility, immune cell development, and atherosclerosis, and a few studies have even suggested a role for ACE in generating an effective immune response.

The researchers used experimental mice (ACE 10/10 mice) that express ACE only in their macrophages. The findings were quite intriguing.
When injected with aggressive melanoma cells, normal mice developed large melanoma tumors whereas ACE 10/10 mice developed only very small tumors. The resistance of ACE 10/10 mice to melanoma growth was confirmed using several different melanoma cell lines and by using different strains of mice expressing high levels of ACE in macrophages. Interestingly, the small tumors of ACE 10/10 mice contained significantly higher numbers of white blood cells, suggesting a large anti-tumor immune response.

To confirm the existence of an ACE-specific anti-tumor immune response, normal mice were depleted of their bone marrow and transplanted with ACE 10/10 bone marrow. When the transplanted normal mice were then injected with melanoma cells, they too were able to control tumor growth. The immune response involved not just the ACE-expressing macrophages but also increased numbers of cytotoxic T cells and levels of immune-activating chemicals and decreased levels of immune-suppressing chemicals. Finally, the ACE 10/10 macrophages alone could direct the immune response and convey protection as direct injection of these cells into melanoma tumors of normal mice yielded decreased tumor size.

It will be very interesting to learn what further research reveals about how ACE enhances the immune system.

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How cells can cheat death

Sunday, July 1, 2007

To begin with, we have to point out that for a cell to cheat death is usually not a good thing. The reason is that cell death is usually the result of a process called apoptosis, and this process has been carefully developed (by evolution) to dispose of cells that have become "sick" because of infection (by a virus) or damage that can occur to the cell's DNA in a variety of ways. Your body needs healthy cells to function, not sick ones. Especially it does not need cells with damaged DNA, which may well become cancerous.

Apoptosis is needed in other contexts as well. In a developing embryo apoptosis is needed to remove unnecessary tissue. In addition, failure of apoptosis can lead to autoimmune diseases as well as cancer. (This is why some anti-cancer drugs are also able to treat some autoimmune diseases.)

The following research announcement, which we'll look at in more detail, has a nice capsule summary of apoptosis.

Cells Re-energize To Come Back From The Brink Of Death
Apoptosis is triggered by a variety of factors, including gene mutations that can make the cell become cancerous. During apoptosis, the membrane covering the cell's mitochondria develop holes and leak a molecule called cytochrome c, which triggers the activity of enzymes called caspases. In turn, caspases trigger a series of events that kills the cell.

To amplify a little, here are some of the conditions that can initiate a cell's apoptosis program:

  • P53 protein may detect damaged DNA during the G1 phase of the cell division cycle. If it does not prove possible to repair the damaged DNA, P53 can invoke apoptosis.
  • The cytokine TNF (tumor necrosis factor) produced by the immune system (specifically, activated macrophages) is an external signal to initiate apoptosis. As the name implies, this is another anti-cancer mechanism.
  • Signals produced by cytotoxic T cells of the immune system can also induce apoptosis. This may occur in response to a virus-infected cell. (Much more on T cells: here.)

However, there is a weak spot in the apoposis process: it requires the presence of caspase enzymes. If something has blocked production of essential caspases (which some tumors are able to do), then apoptosis won't work.

Because of this, nature (i. e. evolution) has provided a backup mechanism for programmed cell death, one that does not rely on caspases. The mechanism is called, appropriately, caspase-independent cell death (CICD), and the research announcement mentioned above has this to say about it:
The process by which the membranes develop holes--mitochondrial outer membrane permeability (MOMP)--is often the "point of no return" for self-destruction, said Douglas Green, Ph.D., chair of the St. Jude Immunology department and the study's senior author. MOMP triggers apoptosis, but if apoptosis fails because there is no caspase available, the backup program called caspase-independent cell death (CICD) takes over the process.

Previous research has shown that cells that become cancerous lack caspase and other proteins needed to support apoptosis after MOMP releases cytochrome c. But this victory over death is short-lived if CICD is activated.

Unfortunately, tumors (successful ones anyway) eventually develop the ability to cheat this death program as well:
However, some cancerous cells not only dodge death from apoptosis by eliminating caspase activation, but they also foil CIDC. "Our study sought to understand how a cancer cell without caspase activation bypasses CICD as well," Green said.

The St. Jude team discovered that a cell that lacks caspase activation and cannot undergo apoptosis increases the levels of an enzyme called GAPDH in order to counteract CICD. GAPDH appears to prevent CICD by supporting the functioning of the mitochondria and triggering the activity of certain genes that prevent or repair cell damage. The findings also suggest that the increase in GAPDH provides energy to increase autophagy--the process by which a cell "chews up" debris and broken components, such as damaged mitochondria. After disposing of damaged mitochondria the cell can replace these vital components.

"We found that in the absence of caspase activation, cells that avoided CICD took about a week or so to begin multiplying again," Green said. "This might represent the time it takes for the cell to restore enough mitochondria to allow the cell to function normally."

Cancer cells are (unfortunately) amazing in their resourcefulness. Of course, this results from a kind of evolutionary process, in which cancer cells that are successful at cheating death and reproducing are those which have developed, by chance, the necessary mutations.

The role played by mitochondria and caspases in apoptosis is quite important for an understanding of both cancer and autoimmune diseases. It's worth remembering the connection, since further research will certainly tell us a lot more about these interrelated processes. Here's an example of earlier research on the subject: Proteins are Key to Cell Death in Heart Disease, Stroke and Degenerative Conditions

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