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Male homosexuality

Sunday, June 29, 2008

Doesn't it really suck to be a religious adversary of homosexuality these days? All their favorite arguments against genetic predispositions in some people for same-sex attraction are crumbling into dust. But then, when has their position ever had a foundation in the use of reason?

One of the favorite arguments against homosexuality is that it couldn't survive evolutionary selection, since only male-female couples can reproduce naturally.

It has previously been shown (2004), by one of the same researchers involved with a follow-on study, that females in the maternal line of male homosexuals were more fertile than average. This suggests that such females have some genetic characteristics that at the same time help them have more offspring and also to have more male offspring with homosexual inclinations than the overall average. This should be enough to allow homosexual males to stay in the population at some level, even if they never actually have children of their own.

Of course, questions still remained. What evolutionary model of this situation would actually show statistically that homosexual males would continue to persist in the population? And what characteristics of certain females promote both higher fertility and higher proportion of homosexual male offspring?

There are now some answers:

Male Homosexuality Can Be Explained Through A Specific Model Of Darwinian Evolution, Study Shows (6/17/08)
An Italian research team, consisting of Andrea Camperio Ciani and Giovanni Zanzotto at the University of Padova and Paolo Cermelli at the University of Torino, found that the evolutionary origin and maintenance of male homosexuality in human populations could be explained by a model based around the idea of sexually antagonistic selection, in which genetic factors spread in the population by giving a reproductive advantage to one sex while disadvantaging the other.

Male homosexuality is thought to be influenced by psycho-social factors, as well as having a genetic component. This is suggested by the high concordance of sexual orientation in identical twins and the fact that homosexuality is more common in males belonging to the maternal line of male homosexuals. These effects have not been shown for female homosexuality, indicating that these two phenomena may have very different origins and dynamics.

Male homosexuality is difficult to explain under Darwinian evolutionary models, because carriers of genes predisposing towards male homosexuality would be likely to reproduce less than average, suggesting that alleles influencing homosexuality should progressively disappear from a population. This changed when previous work by Camperio Ciani and collaborators, published in 2004, showed that females in the maternal line of male homosexuals were more fertile than average.

It was necessary to consider specific models of traits and genetic inheritance in order to eliminate any (and possibly all) that were inconsistent with existing data:
Challenged by all these empirical data, the authors of the new study considered a range of different hypotheses for the genetic diffusion of male homosexuality. These included: the genetic maternal effects on sons, the heterozygote advantage (as is found in malaria resistance), and "sexually antagonistic selection." The latter is a particular aspect of Darwinian evolution, in which genetic factors spread in the population by giving a reproductive advantage to one sex while disadvantaging the other. ...

To discover and clarify the dynamics of the genetic factors for homosexuality, the researchers had to screen a large set of models and exclude them one by one. They concluded that the only possible model was that of sexually antagonistic selection. The other models did not fit the empirical data, either implying that the alleles would become extinct too easily or invade the population, or failing to describe the distribution patterns of male homosexuality and female fecundity observed in the families of homosexuals. Only the model of sexually antagonistic selection involving at least two genes -- at least one of which must be on the X chromosome (inherited in males only through their mother) -- accounted for all the known data.

The results of this model show the interaction of male homosexuality with increased female fecundity within human populations, in a complex dynamic, resulting in the maintenance of male homosexuality at stable and relatively low frequencies, and highlighting the effects of heredity through the maternal line.

It makes a lot of sense, when you stop to think about it for even a moment, that a genetic factor favoring male homosexuality should be on a chromosome (X) that females have one more copy of than males. In that way, the factor can potentially be inherited, regardless of what her mate's genetics are. It also helps if the genes, whatever they are, tend to make female offspring more fertile, even if the male offspring are less fertile (because of homosexuality).

So what sort of characteristic might it be that favors females by making females more likely to reproduce but males less likely? Another report on this research spells it out:

"Gay Genes" May Be Good for Women (6/18/08)
Camperio Ciani's team suggests that these gay genes may actually increase how attracted both men and women are to men rather than making gay men more "feminine," as some researchers had earlier proposed. Although this is bad for male fertility, it is good for female fertility and allows such genes to survive at low but stable rates in a population, the authors say.

Dean Hamer, a behavioral geneticist at the National Cancer Institute in Bethesda, Maryland, who pioneered the search for gay genes, calls the study "an elegant mathematical analysis." He adds that the team has come up with a "simple solution" to the Darwinian paradox posed by homosexuality: "What is a 'gay gene' in a man is a 'superstraight gene' in a woman," he says.

With the evolutionary questions about male homosexuality out of the way, it's interesting to note that there is also recent evidence about the physiological nature of it. That is, there are physical differences between the brains of homosexual and non-homosexual individuals, both male and females. And further, the brains of homosexual individuals are different in ways that make them more like the brains of non-homosexuals of the opposite sex.

Symmetry Of Homosexual Brain Resembles That Of Opposite Sex (6/17/08)
Swedish researchers have found that some physical attributes of the homosexual brain resemble those found in the opposite sex. ...

Some psychological tests have shown differences between men and women in the extent to which they employ the brain’s hemispheres in verbal tasks. Other research has hinted that homosexuals may exhibit the tendencies of the opposite sex in brain behavior unrelated to sexual activity.

Ivanka Savic and Per Lindström, of the Department of Clinical Neuroscience at the Karolinska Institute in Stockholm, Sweden, now report that the brains of heterosexual men and homosexual women are slightly asymmetric — the right hemisphere is larger than the left — and the brains of gay men and straight women are not.

Positron emission tomography (PET) scans taken by the researchers also show that in connectivity of the amygdala (which is important for emotional learning), lesbians resemble straight men, and gay men resemble straight women.

A couple of remarks about this. First, these results don't have much to do with those of the research discussed earlier, in that they don't indicate how females who tend to have male homosexual children might be more attracted to men. But they aren't inconsistent, either. Second, although there are physiological differences, these could be due to exposure of the fetus to sex hormones in the womb, rather than to genetic factors.

In fact, it is possible that genetic factors aren't involved in male homosexuality per se. It could be that the genetic factors carried by females who tend to have male homosexual children are responsible for the hormonal environment in their wombs that pruduces both homosexuality and the brain differences just noted. But this may be unlikely, as the effect would have to be different, depending on the sex of the child – female children would still get brain characteristics atypical of females, yet the same attraction to males as their mothers have.

Sexuality is complicated.

More news reports about this:

An interesting question that still remains is: what does the evolutionary and physiological evidence say about female homosexuality? Not being lesbian, or even female, I don't have any particularly good insight into this. Just speculating, I would guess that the physiological factors tipping a female towards preferring another female rather than a male as a partner are complicated.

However, it could be as simple as that, as in the research discussed above, homosexual females have, like straight males, neural wiring that results in attraction to females. So that, consequently, there are few natural inhibitions, and some rewards, for females to seek other females for pair bonding.

Furthermore, since females can easily get pregnant with only brief (and usually ready, willing, and able) assistance from males, it would not be difficult for paired females to raise children together. Perhaps even less stress than trying to do the same with a male partner who has a roving eye. The males, for their part, might be just as happy not to assume the burdens of fatherhood, so they can go off hunting (for game, or more females) with their pals.

The evolutionary position of males and females who pair with their own sex just isn't symmetrical. Male couples cannot have children of their own, without the substantial assistance of a female for an extended period of time (especially if you count, as you must, a couple years for breast feeding.) But female couples just don't have such a problem. Life's not fair. This lack of similar evolutionary obstacles suggests a larger tendency towards bisexuality, at least, in females, which seems to be the case.

Update, 7/12/08:

A recent study of twins concluded that homosexuality results from a mixture of genetic and environmental factors: Homosexual Behavior Largely Shaped By Genetics And Random Environmental Factors.

A somewhat earlier study by one of the authors of the twin research found that male homosexuals navigate in virtual reality in a way similar to (straight) females: Gay Men Navigate In A Similar Way To Women, Virtual Reality Researchers Find

Update, 8/20/08:

Here's more recent research from Camperio Ciani and colleagues:

Bisexuality passed on by 'hyper-heterosexuals' (8/15/08)

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More resveratrol hoopla

Saturday, June 28, 2008

Resveratrol is in the news. Again.

My last major note about resveratrol is here, way back last September. How time flies. I also mentioned it more briefly here, in May, in connection with cancer. (Where its effect may involve facilitating apoptosis of tumor cells.)

But resveratrol's now back in the news again, so I guess it's time for an update.

As you recall, resveratrol seems to have a number of properties that confer health benefits. For example, it is thought to be an antioxidant, an anti-inflammatory, and perhaps to activate sirtuin enzymes, which may help produce an effect similar to calorie restriction.

The big question is whether you can get the benefits from the amount of the stuff you can get in a dose of reasonable size, for a reasonable price, and without having to drink gallons of wine per day (not a great idea).

Now we have recent reports of two more research results dealing with resveratrol. One suggests a benefit in countering obesity, and the other concerns anti-aging properties that mimic calorie restriction.

Here's the finding on obesity, the relation to which of resveratrol I cannot recall having heard bandied about before:

Red Wine's Resveratrol May Help Battle Obesity (6/16/08)
Resveratrol, a compound present in grapes and red wine, reduces the number of fat cells and may one day be used to treat or prevent obesity, according to a new study.

Past research found that resveratrol protected laboratory mice that were fed a high-calorie diet from the health problems of obesity, by mimicking the effects of calorie restriction. Researchers at the University of Ulm in Germany wanted to know if resveratrol could mimic the effects of calorie restriction in human fat cells by changing their size or function. The German team used a strain of human fat cell precursors, called preadipocytes. In the body, these cells develop into mature fat cells. ...

In the cell-based study, they found that resveratrol inhibited the pre-fat cells from increasing and prevented them from converting into mature fat cells. Also, resveratrol hindered fat storage.

One would certainly expect effects like that, if they can be reproduced in living humans, to be helpful in countering obesity. But there were two other beneficial effects as well:

We've discussed both of these subjects before: IL-6 and inflammation were discussed here, while adiponectin was discussed here and here.

But the intriguing connections don't even stop there. Another report on the same research suggests that the effects related to fat cells may be mediated through sirtuin proteins:

Red wine component resveratrol might fight obesity, lab tests show (6/16/08)
Resveratrol’s mechanism of action is not entirely clear, but the compound seems to activate at least one member of a family of proteins called sirtuins. While also poorly understood, some sirtuins show up in fat cells.

Previous work showed that low levels of sirtuins allowed fat cells to add fats and to proliferate freely from nascent to mature stages, a recipe for weight gain. Conversely, that work also showed that an increase in sirtuins — in that case the compound Sirt2 — kept stem cells from maturing into full-fledged fat cells and inhibited mature fat cells from filling with fats.

In the new study, resveratrol’s good effects failed to emerge in either nascent or mature fat cells engineered to lack a sirtuin called Sirt1, Wabitsch said.

As potential therapeutics, “the sirtuins are a new class in the armamentarium of diabetes and pre-diabetes management,” says Henry Anhalt, a pediatric endocrinologist at Animas Corp. in West Chester, Pa., who wasn’t involved in this study. Sirtuins seem to curb the risk of obesity, cardiovascular disease and inflammation, all of which have been correlated with development of diabetes and its complications. The finding that resveratrol seems to work through a sirtuin (Sirt1) opens up new research opportunities, he says.

As previously noted, I've had a lot to say about sirtuins, which you can refer to here.

The second recent study, which appeared about two weeks before the one just discussed, involved experiments with mice that explicitly compared the effects of resveratrol and calorie restriction:

Substance In Red Wine, Resveratrol, Found To Keep Hearts Young (6/4/08)


This research sharpens results that have previously been found, and also shows that the required dose of resveratrol may not be unreasonable:
Previous research has shown that resveratrol in high doses extends lifespan in invertebrates and prevents early mortality in mice given a high-fat diet. The new study, conducted by researchers from academia and industry, extends those findings, showing that resveratrol in low doses and beginning in middle age can elicit many of the same benefits as a reduced-calorie diet.


The group explored the influence of the agent on heart, muscle and brain by looking for changes in gene expression in those tissues. As animals age, gene expression in the different tissues of the body changes as genes are switched on and off.


Another report stresses the overlap between the effects of calorie restriction and of resveratrol:

Red wine compound seen protecting heart from aging (6/4/08)
Using a method that permits simultaneous analysis of thousands of genes at the same time, the researchers found a huge overlap in the genes whose activity were changed by resveratrol and caloric restriction.

They looked at the heart, brain and muscles, and said that the effect of resveratrol was strongest in the heart but did prevent some aging-related changes in the other tissues.

A similar news release on this research mentions an upcoming Phase I human clinical trial that will study the effects of resveratrol on older humans:

Substance in red wine found to keep hearts young (6/5/08)


It also calls attention to the possible longevity-promoting effects of resveratrol on the mitochondria of cells:


New York Times science writer Nicholas Wade (who, in earlier articles, had questioned the necessary dosage of resveratrol, see here) has a cautionary article that puts this research into context of other work on resveratrol and sirtuins. Among other points, he notes that there is still plenty of room to question whether resveratrol, or something similar, will actually have health benefits in humans, for example:

New Hints Seen That Red Wine May Slow Aging (6/4/08)


More news reports about this:

Update, 7/16/08: There's more recent news about resveratrol here.

Further reading:

A Low Dose of Dietary Resveratrol Partially Mimics Caloric Restriction and Retards Aging Parameters in Mice – abstract and complete technical article describing the mouse study

Low-dose resveratrol as a calorie restriction mimetic – 6/12/08 blog post with further comments on the mouse study and associated issues

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Sunday, June 22, 2008

It's always interesting to find out that important hormones and proteins play multiple disparate roles in an organism. Such a finding suggests that problems in one area may be related to problems in very different areas.

I suppose everyone knows that serotonin is "that brain chemical" which is messed up somehow when you're depressed and need some Prozac. But it turns out there's more to it than just that.

Here are some recent examples.

The first may seem somewhat surprising, since it relates to metabolism, and it isn't obviously connected with mood, with which serotonin is commonly linked.

Actually, a link between mood and hunger via serotonin shouldn't be so surprising. The chemical name for serotonin is 5-hydroxytryptamine (or 5-HT for short). This hints at its chemical relationship to the amino acid trytophan. Although the connection between tryptophan and post-prandial drowsiness is more complicated than generally supposed, there is a connection, and synthesis of serotonin (and melatonin) from tryptophan is involved. (Have you ever felt grumpy or depressed, or had trouble sleeping, while dieting? The relative lack of tryptophan is what's responsible.)

But that's not what the recent research is about:

Eating And Weight Gain Not Necessarily Linked, Study Shows (6/3/08)
You may not be what you eat after all. A new study shows that increased eating does not necessarily lead to increased fat. The finding in the much-studied roundworm opens the possibility of identifying new targets for drugs to control weight, the researchers say.

The discovery reveals that the neurotransmitter serotonin, already known to control appetite and fat build-up, actually does so through two separate signaling channels. One set of signals regulates feeding, and a separate set of signals regulates fat metabolism. The worm, known scientifically as Caenorhabdtis elegans, shares half of its genes with humans and is often a predictor of human traits.

Serotonin affects how hungry an organism feels. But there's more to it than that. Apparently, serotonin also affects how cells metabolize fat.

An abstract of the original research summarizes this latter effect:

Serotonin Regulates C. elegans Fat and Feeding through Independent Molecular Mechanisms
Serotonergic fat regulation is dependent on a neurally expressed channel and a G protein-coupled receptor that initiate signaling cascades that ultimately promote lipid breakdown at peripheral sites of fat storage. In turn, intermediates of lipid metabolism generated in the periphery modulate feeding behavior. These findings suggest that, as in mammals, C. elegans feeding behavior is regulated by extrinsic and intrinsic cues. Moreover, obesity and thinness are not solely determined by feeding behavior. Rather, feeding behavior and fat metabolism are coordinated but independent responses of the nervous system to the perception of nutrient availability.

This news report explains it even better:

Mood hormone may affect fat, U.S. study finds (6/3/08)
Serotonin may help the body decide whether to burn off excess calories, or store them as fat, Ashrafi said. ...

"It has been known for a long time that increasing serotonin causes fat reduction," Ashrafi said.

"At the molecular level we are trying to understand what is the mechanism that allows that to happen. What we discovered in the worm is that those mechanisms can be separated from the mechanisms that mediate the effects of serotonin on appetite."

The research found serotonin levels affected the worms' appetite, but they also affected how much fat the worms accumulated, and this was via a separate process.

If the worms detect a food shortage, their metabolisms shift and they store more fat.

More: The Skinny on Fat: You're Not Always What You Eat (6/4/08)

The second recent research report on serotonin concerns its effects on mood, but in rather more complex ways than simply in terms of "depression". Serotonin also seems to affect feelings of fairness, anger, and aggression in social decision-making. Significantly, with respect to the research just discussed, these feelings are modulated by recent feeding experience. And there are ramifications for impulsivity and obsessive tendencies.

Serotonin Link To Impulsivity, Decision-making, Confirmed (6/5/08)
New research by scientists at the University of Cambridge suggests that the neurotransmitter serotonin, which acts as a chemical messenger between nerve cells, plays a critical role in regulating emotions such as aggression during social decision-making.


Their findings highlight why some of us may become combative or aggressive when we haven't eaten. The essential amino acid [i.e. tryptophan] necessary for the body to create serotonin can only be obtained through diet. Therefore, our serotonin levels naturally decline when we don't eat, an effect the researchers took advantage of in their experimental technique.

So the researchers reduced serotonin levels in volunteer subject by manipulating their diet. In order to probe the social effects of this, the researchers used a laboratory game called the "ultimatum game", which is something that social psychologists now like to use in order to study social variables of trust and sense of fairness. (There's much that's interesting to say about this game, as far as instinctive ideas of morality and ethics are concerned, but that must wait for another time.)
The researchers were able reduce brain serotonin levels in healthy volunteers for a short time by manipulating their diet. They used a situation known as the 'Ultimatum Game' to investigate how individuals with low serotonin react to what they perceive as unfair behaviour. In this game one player proposes a way to split a sum of money with a partner. If the partner accepts, both players are paid accordingly. But if he rejects the offer, neither player is paid.

Normally, people tend to reject about half of all offers less than 20-30% of the total stake, despite the fact that this means they receive nothing - but rejection rates increased to more than 80% after serotonin reductions. Other measures showed that the volunteers with serotonin depletion were not simply depressed or hypersensitive to lost rewards.

Contrary to how some news reports have described the results of this experiment, the increased rate of rejecting unfair was not found to be related to overall mood or perception of fairness, as this account notes:

Deal or No Deal? (6/5/08)
The lack of tryptophan did not affect the subjects' general moods or their perceptions of the fairness of an offer, the team reports online today in Science. It did, however, appear to make people more likely to reject unfair offers.
Indeed, according to the published abstract of the research:

Serotonin Modulates Behavioral Reactions to Unfairness
Participants with depleted 5-HT levels rejected a greater proportion of unfair, but not fair offers, without showing changes in mood, fairness judgments, basic reward processing, or response inhibition.
Additional reports: here, here, here

Further reading:

Low Serotonin Increases Desire To Punish Unfairness (6/5/08) – blog post

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Hubble’s sweeping view of the Coma Galaxy Cluster

Monday, June 16, 2008

Hubble’s sweeping view of the Coma Galaxy Cluster (6/10/08)




Abel 1656 (Coma Cluster) – Click for 1280×909 image

More: here, here

Mystery deepens over origin of biggest black holes

Sunday, June 15, 2008

Mysteries are popular, so here's a good one, about another popular subject, black holes.

Mystery deepens over origin of biggest black holes (5/19/08)


Note that this isn't the only way that black holes could have formed, not even black holes of about this size. That's good, because what this study seems to show is that it would be difficult for a black hole formed from a collapsed early star to accrete enough matter to grow into a supermassive black hole (SBH).


Early famine


Let's just suppose this simulation result makes the formation of SBHs from such seeds very unlikely. Are there other reasonable possibilities?

Sure there are. One is that black holes don't exist at all, so neither do SBHs. Never mind that most galaxies seem to contain very massive objects, whose mass is 105 solar masses or more. (Normally written as 105M.) The Milky Way itself has a black hole at its center, whose mass is estimated at 3.7×106M.

Such massive objects need an explanation too, which would have at least the same difficulties as for SBHs. But we've already noted that the evidence for black holes is very solid (see here), so let's rule this out.

Here's another recent hypothesis:

Biggest black holes may grow inside 'quasistars' (11/29/07)
The biggest black holes in the universe might have grown within the bellies of giant stars, a new study suggests. If these hole-bearing "quasistars" exist, then they might be bright enough to see from across the universe.

Quasistars are one attempt to explain the existence of supermassive black holes, which astronomers have detected at the hearts of most large galaxies, and whose origin is still unknown.

It is calculated that this could account for objects up to 104M in size. One problem here is that possible quasistars have never actually been observed, and observation is expected to be difficult at best, since they would have formed so soon after the big bang, and consequently now be very distant (like more than 1010 light-years).

Another problem is that SBHs can be far larger than this. The largest SBH known so far is about 1.8×1010M. (See here, here.) SBHs that formed in quasistars would still need to accrete something like 106 times their initial mass to grow into the largest known SBH, let alone any larger ones that might be out there. (For comparison, the mass of the Milky Way, a medium-size galaxy, is about 1012M. See here, here.)

So a quasistar origin for SBHs doesn't seem too likely either, but if you want to pursue it further, the relevant paper is here.

We haven't yet even mentioned one obvious possibility: primordial black holes (PBHs). That is, black holes that formed directly very soon after the big bang itself. Exactly at what time this might have been depends very much on how PBHs might have formed, and there's plenty of uncertainty about that.

In fact, we have no evidence yet that PBHs exist at all. Since we don't know exactly how they might have formed, we don't know how big they might be, which strongly affects what we should look for. If PBHs were small enough, they should eventually "evaporate", as Stephen Hawking suggested, by the process of Hawking radiation.

There's much debate as to what happens when a sufficiently small PBH evaporates completely (see here, here, here, here, here). But such an event is generally supposed to include emission of gamma-rays, and these might be detected by the newly-launched GLAST mission. (See here.)

The most likely scenario for the formation of a PBH is as a result of gravitational collapse of overdense regions existing because of density fluctuations dating from the earliest instants after the big bang. Since fluctuations are the key, formation of PBHs is governed by probability, and the larger the PBH, the lower its probability, and hence the fewer that form altogether. While there's no obvious upper limit to the size of a PBH, the formation of one around 104M would be very improbable. Too improbable? No one knows.

Other mechanisms hypothesized for formation of PBHs tend to feature rather exotic things like topological defects (cosmic strings or domain walls) or certain kinds of phase transitions.

But this is all so speculative that it's not much help for evaluating whether PBHs might make a good source of SBHs. A great reference for stuff about PBHs is this: Primordial Black Holes: Do They Exist and Are They Useful?.

The bottom line is that closer study of SBHs, which almost certainly do exist, should eventually lead us to some concrete evidence for things that are presently much more speculative.

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IGF-1, calorie restriction, exercise, and longevity

Saturday, June 14, 2008

Loyal readers here (both of you) may recall that back here I mentioned the hormone IGF-1 and promised to deal with it more throughly. The occasion was that IGF-1 is a growth factor, like BDNF.

Basically, a growth factor is a protein for signaling between cells. Growth factors typically bind to specific receptors on a cell's surface, in order to promote cell survival, growth, or proliferation.

The following recent news item now gives me an excuse to make good on my promise:

Hormone May Hold Key To Helping Elderly Men Live Longer (5/27/08)
Elderly men with higher activity of the hormone IGF-1--or insulin-growth factor 1--appear to have greater life expectancy and reduced cardiovascular risk, according to a new study.

IGF-1 is a hormone similar in molecular structure to insulin. It is released from the liver and plays an important role in childhood growth and continues to have anabolic effects in adults. ...


So, does that mean we need to find ways to increase our body's IGF-1 production in order to extend lifespan? Well, not necessarily. It's more complicated than that, as we'll see shortly.

Any hint of longevity enhancement, of course, is something worth paying attention to, but in the case of IGF-1, there's a lot more to the story. It's actually kind of a big deal for several additional reasons.

To begin with, the full name of the hormone is insulin-like growth factor. It is so-named because, as the news item mentions, its molecular structure is similar to that of insulin.

But that's just the beginning of the similarity. Both IGF-1 and insulin affect metabolism. In fact, IGF-1 can bind to the same receptor that insulin does, although a lot less strongly. That, and the not coincidental structural similarity to insulin suggest that perhaps, sometime far back in evolution, the same gene may have coded for some ancestor of both insulin and IGF-1.

If you take into account a striking fact about the IGF-1 receptor, this hypothesis of a common origin for insulin and IGF-1 becomes even more intriguing. The fact is that the (gene for the) IGF-1 receptor is a homologue of the daf-2 gene of the nematode Caenorhabditis elegans (as is the gene for the insulin receptor also). In fact, DAF-2 (the protein product of daf-2) is the only insulin-like receptor in nematodes, so biologists now regard daf-2 as the ancestor of the mammalian receptors for IGF-1 and insulin.

I first mentioned this relationship back here, and went into more detail here, in connection with understanding the effect of sirtuin proteins on aging and longevity of C. elegans.

But the "coincidences" don't stop there. The important function of a receptor is the effect it has, when activated, upon signaling downstream inside the cell. All of the receptors we're talking about here are of the sort called tyrosine kinase receptors. Let's unbundle that term. Tyrosine is one of the 20 amino acids that make up proteins. A kinase is a type of protein enzyme whose function is to attach phosphate groups to specific kinds of amino acids in other proteins. This process is called phosphorylation. When another protein of the right sort is phosphorylated, it becomes able to act as a tyrosine kinase itself, and go on to affect yet other proteins.

This whole process is called signal transduction. The process begins (in the case here) with a receptor tyrosine kinase, which is a cell surface receptor protein that is also a tyrosine kinase – for example DAF-2, and the receptors for IGF-1 and insulin. There may be a number of intermediate steps, but the eventual result is the phosphorylation of a transcription factor, which enters the cell nucleus and facilitates the transcription of certain genes in order to produce new proteins.

In C. elegans, DAF-16 is the transcription factor that is activated by signaling mediated by DAF-2. We discussed DAF-16 in the aforementioned posts here and here. DAF-16 belongs to a family of transcription factors called forkhead box proteins. We have discussed these before too, or rather the subclass called FoxO transcription factors.

We're getting pretty far into the technical weeds here, so if you want more details on this stuff, refer to the earlier posts.

To make the long story short, the effects of the external signaling hormones like insulin and IGF-1 ultimately result from proteins coded for by the genes expressed because of the appropriate transcription factors that were activated by the signaling cascade. There are probably many proteins involved, and sorting them all out, figuring out how they collectively affect longevity, is very much an ongoing project.

The story is interesting to understand because longevity is one of its main themes. In addition to the news item already mentioned, there's more recent news with the same theme. Here are summaries of some of these research announcements:

When It Comes To Living Longer, It's Better To Go Hungry Than Go Running, Mouse Study Suggests (5/14/08)
It is once again verified that a low-calorie diet can extend the lifespan of rodents. This benefit is beyond what can be achieved with a higher-calorie diet offset by exercise. However, rats that consumed the most calories, and has less longevity, also had the highest levels of IGF-1. Rats that consumed the fewest calories had the best longevity and the lowest levels of IGF-1. Exercise could only partially counteract the higher IGF-1 levels and reduced longevity of rats on a high-calorie diet. In this study, IGF-1 levels were inversely correlated with longevity. This is a "live-fast, die-young" scenario, which is especially typical of rodents, but not necessarily of humans.

More on this study: here

Shorter Women May Have Very Long Lives: Gene Mutation Found (3/4/08)
This study focused attention on the (adult) daugheters of especially long-lived Ashkenazi Jews. A control group consisted of daughters of the same age as the others, but whose families had no history of unusual longevity. The finding was that female children of long-lived individuals (aged 95-110) were on average 2.5 cm shorter than female controls. It was also found that both the centenarians and their daughters were much more likely than the controls to have mutations in the genes for their IGF-1 receptors. However, the daughters also had blood plasma levels of IGF-1 that were 35% higher than the levels in the control group. The interpretation is that the higher IGF-1 levels were due to an attempt to compensate for disruption of IGF-1 signaling due to irregularities of the receptor proteins. This would be consistent with a number of animal studies in which reduced IGF-1 signaling correlates with increased longevity.

More on this study: here, here, here

Interestingly enough, IGF-1 had already been recognized to have an effect on body size – in mice and dogs. The dog research is described here:

One gene between tiny dogs and giant ones? (10/13/06)
Nate Sutter, a geneticist at the National Human Genome Research Institute in Bethesda, Maryland, wanted to know the reason why big dogs, such as Irish wolfhounds, can grow up to 50 times larger than other members of their own species, such as chihuahuas. So he started out looking at large and small dogs of one breed — the Portuguese water dog. ...

The team found that one of the few differences in these Portuguese water dogs occurred in a gene called 'insulin-like growth factor 1', or Igf-1 .

This is one of many genes already known to influence the size of mice: when Igf-1 is knocked out, the animals grow up to be mini-mice.

(The article is subscription-only, but you can find another reference to it here.)

The researchers went on to do further analysis of the IGF-1 gene in many different dog breeds of all sizes, and also in foxes and wolves. They found that almost all of the small breeds had the same variant of the IGF-1 gene as the small Portuguese water dogs had, while almost none of the large breeds had that variant. The team concluded that the IGF-1 variant in small breeds is responsible for the difference because it reduces production of the growth factor.

This should also explain what dog people have always known – that small breed dogs generally live longer than large ones.

Here's a later report of the same research:

What Makes Little Dogs Small? Researchers Identify Gene Involved In Dog Size (4/5/07)
In their study, researchers explored the genetic basis for size variation among dogs by comparing the DNA of various small dog breeds, including Chihuahuas, Toy Fox Terriers and Pomeranians, to an array of larger dog breeds, including Irish Wolfhounds, Saint Bernards and Great Danes. Their investigation found that variation in one gene - IGF-1, which codes for a protein hormone called insulin-like growth factor 1 - is very strongly associated with small stature across all dog breeds studied.

Further reading:

Scientists Explore Queen Bee Longevity (5/8/07) – press release describing research on various factors, including IGF-1 signaling, in queen bee longevity

Mechanisms of lifespan regulation by IGF-I (2/25/08) – blog post that considers some of the paradoxical effects of IGF-1 that may be beneficial in some ways but also shorten lifespan

Not so fast, daf-2: IGF-I is all kinds of good for you (1/23/08) – another blog post on the paradoxical effects of IGF-1

IGF-1 attenuates cardiac aging (11/15/06) – blog post about research on cardioprotective properties of IGF-1

It’s not easy being wee: Does IGF-1 deficiency slow down the brain? (8/30/06) – one more blog post on paradoxical effects of IGF-1

A Single IGF1 Allele Is a Major Determinant of Small Size in Dogs – 4/6/07 research article in Science (sub. rqd.)

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Bdelloid rotifers

Tuesday, June 10, 2008

The bdelloid rotifers are certainly in the news a lot recently.

They may not be into sex very much, but it turns out they are world-class gene snarfers.

No sex, but plenty of gene transfer




So the first question one has is, how have all these genes from totally different species gotten into the bdelloid genome? The most likely answer is: as a direct consequence of how bdelloids are able to survive such traumatic events as complete dessication or levels of radiation deadly to almost all other species.

Apparently bdelloids are able to do this because of a nearly unique ability to reconstitute and repair heavily damaged DNA. Evidently, in the process, they sometimes incorporate foreign DNA from other creatures they have eaten, or which may simply be lying around. And since some of this reconstituted bdelloid DNA is included in bdelloid egg cells, which eventually become separate individual animals, it is passed on to subsequent generations.

(Something similar to this process, but on a much smaller scale, occurs in "higher" animals too, such as humans. Our genome is full of remnants of the DNA ("exogenous DNA") of viruses that infected our ancestors unknown millions of years ago.)



From the details mentioned so far, there may be some other things you could be wondering about.

For instance, do any of these foreign genes actually work like normal genes once they've become part of the bdelloid genome? Generally, they do not. But there is evidence that a few foreign genes are sufficiently intact that they are transcribed into messenger RNA. And some of this RNA may even be used to make proteins, such as enzymes to catalyze basic metabolic processes.

Interestingly enough, some bacterial genes that have entered the bdelloid genome now have embedded introns, which is normal for eukaryotic genes, but unheard of in prokaryotic (bacterial) genes. (The introns are like punctuation marks that separate distinct segments of a gene, called exons. This makes it possible to construct a number of different proteins from a single gene, by the process of "alternative splicing".)

Another more general question that might occur to you is: why do asexual animals such as bdelloids have egg cells, like more normal sexual creatures? And how, exactly, do they reproduce, anyhow? The answer is probably that at some time back in the evolutionary history of bdelloids (estimated at 50 to 100 million years ago), bdelloids diverged from a rotifer ancestor species that was sexual, as are many species of rotifers today.

So bdelloids still have egg cells, with paired chromosomes that carry two separate copies of the genome, just as "normal" sexual animals do. However, bdelloid eggs do not undergo the process of meiosis, in which egg cells divide, and the paired chromosomes are separated, to be later combined with chromosomes from another individual during fertilization.

Instead, bdelloid eggs are eventually expelled from the mother's body, and go on to develop into a new individual by parthenogenesis, which also occurs occasionally in a few other species capable of asexual reproduction, such as some insects, fish, snakes, and lizards. (Or even sharks and komodo dragons.)

In case you enjoy thinking about sex, you probably have many other questions about what's up with bdelloids. Answers to a lot of these questions can be found in the following.

Further reading:

Common Aquatic Animal's Genome Can Capture Foreign DNA – another 5/29/08 press release about the research

Water creatures caught stealing DNA – 5/30/08 ABC/Reuters news story on the research

Who needs sex when you can steal DNA? – 5/29/08 Reuters news story

Scientists find promiscuous genes in an asexual animal – informative 5/29/08 article from Science News

Massive Horizontal Gene Transfer in Bdelloid Rotifers – 5/30/08 research article in Science (sub. rqd.)

The Weird Sisters – very informative 6/3/08 New York Times blog article, by Olivia Judson

An Evolutionary Scandal – 11/2000 Harvard Magazine article on bdelloid rotifers

Who Needs Sex (or Males) Anyway? – 3/20/07 PLOS Biology article on bdelloids

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Adiponectin, longevity, and cancer

Sunday, June 8, 2008

Adiponectin is a hormone that is made exclusively in adipose (fat) tissue and secreted into the blood stream. It modulates a number of metabolic processes, such as glucose regulation and production of energy from fatty acids.

We had a long note on adiponectin last September (here), which has turned out to be very popular. That article summarized a number of research results concerning adiponectin that have appeared in the last few years. Undoubtedly, much of the interest in adiponectin is a result of its relevance to such things as weight control, diabetes, inflammation, cardiovascular disease, and kidney disease.

Some research that was reported in April had more to say about the relation to kidney disease:

Fat-cell Hormone Linked To Kidney Disease (4/22/08)
Reduced levels of a hormone produced by fat cells and linked to the development of insulin resistance may also be related to a higher risk of kidney disease, according to a study led by researchers at the University of California, San Diego School of Medicine and Thomas Jefferson University. ...

The new findings show that the hormone, adiponectin, produced by fat cells, circulates in the blood and acts to both suppress inflammation -- known to be a contributor to diabetes and cardiovascular disease -- and to reduce protein in the urine.

"A deficiency in adiponectin could be the major reason why obese patients develop the initial signs of kidney disease," said principal investigator Kumar Sharma.

The research showed that adiponectin promotes proper function of kidney cells called podocytes:
A network of fine capillaries in the kidney acts as a filter to prevent proteins in the blood from being secreted into the urine. This filter is made up of three components, one of which -- the podocyte cell -- serves to regulate albuminuria.

"We discovered that the hormone adiponectin, produced by fat cells, is directly linked to the healthy function of podocytes," said Sharma.

While that's interesting, it's not clear that this activity has much to do with adiponectin's effect on metabolism through favoring the use of fats as a source of energy instead of glucose. This may be a case where an important hormone really does have unrelated effects on different physiological systems.

Earlier research on adiponectin suggested that it served as a signal of low levels of available food calories, and hence caused the body to favor metabolism of stored fat as an energy source. This could well be related to the known effects of calorie restriction on longevity. Indeed, some research from last November suggested that longevity is promoted because metabolism of fat generates a lower level of reactive oxygen species than does metabolism of glucose:

Fat Hormone May Contribute To Longevity (11/21/07)



Given that reactive oxygen species are also linked to increased inflammatory response and DNA damage, and that both of these effects are linked to cancer, it's not too surprising to find that variations in the gene for adiponectin may affect cancer risk:

Gene Variations May Predict Risk Of Breast Cancer In Women (5/2/08)
According to a recent study, led by Virginia Kaklamani, MD, an oncologist at Northwestern Memorial Hospital and assistant professor of medicine, Northwestern University Feinberg School of Medicine, variations of the adiponectin gene, which regulates a number of metabolic processes, may increase a woman’s risk of developing breast cancer. ...

Dr. Kaklamani’s research, which is published in the May 1 issue of Cancer Research, suggests some women are born with different characteristics in the adiponectin gene which can alter its function and increase the risk of breast cancer. This finding, coupled with previous studies that have found a correlation between low levels of adiponectin in the body and cancer risk, suggest adiponectin may be the third gene linked to breast cancer among women with no previous family history of breast cancer. If confirmed through additional studies, adiponectin could be used along with TGF-beta and CHEK2, genes that have already been linked to breast cancer, to create a genetic testing model that will allow clinicians to more accurately predict breast cancer risk.

Further reading:

Happy fat: Calorie restriction modulates adipocyte gene expression – 7/17/07 blog article that discusses research relating calorie restriction to adiponectin

Adipogenic signaling in rat white adipose tissue: Modulation by aging and calorie restriction – abstract of the research discussed in the preceding item.

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GLAST and gamma-ray astronomy

Sunday, June 1, 2008

According to the present schedule, the GLAST gamma-ray telescope mission will be launched next week, on June 5, around noon EDT. If you're reading this before then, you can expect to find quite a bit of news coverage around that date. It's actually kind of a big deal, and I'll summarize some of the reasons for that here.

To begin with, you can find background information on the mission from NASA here and here.

In addition, there have been some good summaries already in science-oriented publications:

You can find good explanations of exactly what GLAST is in most of the above references.

What I'll summarize here are just some of the main objects and phenomena that GLAST is expected to help observe and study.

Gamma-ray bursts
Gamma-ray bursts (GRBs) have been discussed here several times, such as here and here. It is generally agreed that there are several different events that can cause a GRB, and a fair amount is known about the phenomenon already. For instance, the subtype known as a "long" GRB is thought to result from supernova explosions in which a high-energy jet of particles and radiation is emitted in a narrow beam that happens to point in our direction. But as yet we haven't measured the complete spectrum of energy from a GRB of any type. This spectrum can range from a few KeV to hundreds of GeV, and knowing it in detail would help determine the nature of the associated event much more accurately.

Dark matter
The visible universe that consists of luminous objects like stars and galaxies is composed of baryonic matter (mainly protons and helium nuclei). There may be at least as much baryonic matter in the form of diffuse gas that we cannot see. (Recent observations here and here.)

Yet it is essentially certain that the universe actually contains about four times as much matter that we can't detect at all (except by its gravitational effects) as all that baryonic matter put together. This is the dark matter. There are many theories about what this dark matter consists of, but in one of the main classes of theories, the matter consists of "weakly-interacting massive particles" (WIMPs). In most such theories, WIMPs can annihilate each other in pairs, giving off copious quantities of gamma-rays (among other things).

If some such theory accounts for a portion of the dark matter, GLAST will make it possible to estimate properties of WIMPs (e. g. their mass) by observing gamma-rays from locations where dark matter is expected to be concentrated, such as in the center of the Milky Way. This kind of information will complement and help corroborate observations made at the Large Hadron Collider, in which some kinds of WIMPs (if they exist at all) are expected to be created.

Solar gamma-rays
Although our Sun is a relatively weak source of gamma-rays compared to almost everything else mentioned here (even weaker than the Moon, where gamma-rays are produced when cosmic rays strike the surface), several solar events, such as flares and coronal mass ejections do produce gamma-rays. So GLAST will help us better understand solar events of this kind.

Supernova remnants
A large class of gamma-ray bursts are associated with the initial blast of a supernova event, and the gamma-rays from such bursts subside in a matter of minutes. But other gamma-rays may originate by other mechanisms from the supernova remnant long after the original event. Gamma-rays are thought to be produced in such remnants due to particles being accelerated to high energies in the blast and subsequently generating shock waves in the interstellar medium. The shock waves themselves are reasonably well understood, but how the particles are actually accelerated by the supernova blast needs much more elucidation, which GLAST can provide.

Another part of the remnant left over after a supernova is either a stellar-mass black hole, or else a rapidly spinning neutron star. Such a neutron star will produce jets of electromagnetic energy, usually at radio frequencies, and when the Earth is lined up with the jet the object is called a pulsar. These also emit gamma-rays. Since neutron stars are extremely small and dense, they have intense magnetic fields near their surface, and the fields reveal a lot about the nature of matter in the neutron star. The strong fields also convert gamma-rays into electron-positron pairs, so the overall gamma-ray spectrum can give us information about the object's magnetic fields, and about surface features that cause gamma-ray emission.

Supermassive black holes, active galactic nuclei, quasars, blazars
Supermassive black holes are thought to exist at the centers of most or all galaxies. We can estimate that they have masses ranging from 105 to 1010 solar masses, yet there is a great deal more we would like to know about them, such as the process by which they form. (See here.) Most supermassive black holes are thought to be circled by an accretion disk of matter which has been attracted by the object's extreme gravity.

Depending on the amount of matter in the disk, large amounts of energy may be released as the matter falls into the black hole. Our own Milky Way has a smallish object of this sort, with a correspondingly small accretion disk. But if there is much more mass in the disk, one has a bright object called an active galactic nucleus (AGN). AGNs were more plentiful in the early days of the universe, before most of the available nearby matter had been consumed by the black hole, and especially active objects of this kind, usually at great distances, are called quasars.

Like supernovae (from which stellar-mass black holes or neutron stars are formed), supermassive black holes may emit powerful relativistic jets of particles and energy. If such a jet is pointed in our direction, we see an especially bright source, called a blazar. Most of the emitted electromagnetic energy from all these objects is in the gamma-ray part of the spectrum.

So one of the main objectives of GLAST is to measure how this spectrum varies over time, in order to get a better understanding of what is actually going on. For instance, there could be additional confirmation of a model of the relativistic jets as described in this recent research, and perhaps evidence as to whether the particles in the jets are protons or electrons.

Cosmic ray origins
As discussed in detail here, we are finally beginning to clear away some of the mystery surrounding the most energetic ultra-high-energy cosmic rays (UHECRs). But there's a lot more we'd like to know, such as whether these rays are mostly made up of relativistic protons, and what sort of process creates them in the first place. Gamma-rays are produced when UHECRs interact with interstellar gas and dust, so GLAST may be able to give us more information about UHECRs.

Primordial black holes
It is generally suspected that many small black holes (with masses covering a wide range, but much less than the mass of a star) could have been produced in the big bang. These are called primordial black holes. Their existence hasn't yet been confirmed. But Stephen Hawking made a strong case that any black hole will slowly emit weak electromagnetic radiation, due to quantum effects and called Hawking radiation. This radiation should be too weak to be directly observable. However, small primordial black holes should eventually evaporate completely by this process, and at the end disintegrate in a burst of gamma-rays. This is all rather conjectural, but if it happens, it may contribute to a continuous gamma-ray background that can be detected.

Cosmic gamma-ray background
In addition to discrete gamma-ray sources such as GRBs and supernova remnants, there is a diffuse background of gamma-ray photons, much like the cosmic microwave background (CMB), only vastly more energetic. Some of this background may be due to UHECRs, very distant and very powerful (TeV range) gamma-ray sources, or primordial black holes. But who knows what other kinds of sources might be out there? There will probably be some surprises, as well as a lot of useful information to be deduced, just as happened with the CMB.

Possible breakdowns of special relativity
Heading even further into speculative territory, various theorists of quantum gravity have proposed that even special relativity (as well as general relativity too) may break down under various conditions. For example, the speed of light might not be an exact constant, but might instead vary by a slight amount according to the energy carried by individual photons.

Thus not all gamma-ray photons from a GRB would need arrive at precisely the same time, and so any pattern in this radiation would be shifted very slightly depending on what part of the gamma-ray spectrum is observed. Even if the shift is as little as 1/1000 of a second (for photons that may have been travelling for billions of years), GLAST should be sensitive enough to detect the shift. That would certainly be quite a surprise if found.

Further reading:

GLAST Science Writer's Guide – An extremely informative 47-page document (PDF), with detailed descriptions of the relevant science, a glossary, and additional links

Simona Murgia: Dark Matter searches with GLAST – Blog posting that discusses the relevance of GLAST for dark matter searches

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