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Memory and BDNF

Monday, March 31, 2008

Following up on part of this note, where I discussed relationships between memory and stress, it turns out that there are some interesting things known, related to this, which involve a "neurotrophic factor" called BDNF.

In fact, there's quite a lot to say. Let's begin with an explanation of some terms, a little about BDNF, and a look at some research from the past several years on the relationship between BDNF and memory. Later we'll take up more on how stress and depression enter the picture.

A neurotrophin is a type of protein that promotes the survival of neurons – which is in general a pretty good thing. (We'll get to examples in a moment.) One type of neurotrophin, known as a "neutotropic factor", is a growth factor that affects neurons in particular.

More generally, a growth factor is a proteins that signals certain types of cells to survive, differentiate, or grow. A growth factor that helps a cell survive does so by inhibiting programmed cell death. Other growth factors promote cell division, which results in growth of the tissue that contains the affected cells. Yet other growth factors may induce cells to differentiate into cells of a more specialized type.

An important example of a general growth factor is IGF-1, also known as "insulin-like growth factor 1", which we'll be looking at more extensively in upcoming posts.

In this post we're going to consider the specific neurotrophic factor known as BDNF, the brain-derived neurotrophic factor.

Research has shown that BDNF plays a role in memory formation and in the connection between stress and depression. For example, in rats the stress hormone corticosterone seems to decrease the expression of BDNF, and if stress is persistent, this eventually leads to the atrophy of the hippocampus. Since the hippocampus plays an important role in long term memory, this is one way in which stress can negatively impact memory.

Atrophy of the hippocampus has also been found in humans suffering from chronic depression. There is evidence that suggests a deficiency of BDNF may be at least in part implicated in such depression. For example, various factors (such as the neurotransmitter glutamate, exercise, calorie restriction, and antidepressant drugs) are known to stimulate expression of BDNF – and often ameliorate depression as well.

There's a lot of science behind all this. Let's just look at a few research announcements from the past several years to get a feel for the interactions of BDNF and memory.


Key Pathway In Synaptic Plasticity Discovered (5/23/07)
The researchers studied a major developmental event in newborn rodents. A rapid increases in synapse strength and visual circuit refinement occurs quickly after the animal's eyes first open. It was already known that the PSD-95 protein rushes to visual system synapses soon after eye opening. PSD-95 is a scaffold protein that anchors several types of receptors. Some of these receptors are for the neurotransmitter glutamate, and there is also the TrkB receptor for BDNF (and other neurotrophins).

A positive feedback loop is initiated, in which the NMDA glutamate receptor activates BDNF. BDNF then triggers a signaling pathway involving the kinases PI3 and Akt. This pathway leads to more PSD-95 production, completing the loop. The net result is to make synapses more responsive to BDNF, followed by production of additional PSD-95. Once this loop is started at just a few of a neuron's synapses, the rush of PSD-95 to other excitory synapses of the neuron is on. In this way a few very active synapses can prime larger regions of a neuron for long-term synaptic strengthening in response to subsequent stimulation in the newborn animal.

Proteins Necessary For Brain Development Found To Be Critical For Long-term Memory (9/5/06)
This research indicates that BDNF, which is crucial for the growth of brain cells during development, is also equally important for the formation of long-term memories. The study was performed on the common marine snail Aplysia. When the snails are electrically shocked, the neurotransmitter serotonin is released and promotes the formation of long-term memories associated with the shocks. But when the researchers blocked interaction between BDNF and its TrkB receptor, long-term memories did not form, even though serotonin was still released at synapses. This indicates that serotonin alone was not sufficient for long-term memory formation. Short-term memory formation was not affected. Further investigation showed that interfering with the BDNF receptors blocked long-term enhancement of the connections between the brain cells in the reflex circuit normally induced by the shock treatment.

Drug Triggers Body's Mechanism To Reverse Aging Effect On Memory Process (7/27/06)
A class of drugs known as "ampakines" (so-called because they target AMPA receptors) has been under study and development since the early 1990s to deal with neurological conditions, such as schizophrenia, problems of attention span and alertness, and memory impairment associated with dementia and Alzheimer's disease. The research reported here was conducted by a team that included Gary Lynch, who has long been associated with investigation of the biological bases of learning and memory. (See here for more about Lynch and long-term memory.)

In this study, rats were treated for four days with an ampakine drug. Of particular interest was the effect of the drug on the hippocampus of the brain, because of its known importance in the formation of long-term memories. In the hippocampus areas of rats treated with the drug, it was found that (compared to controls) there was a significant increase both of levels of BDNF and of long-term potentiation (LTP) of synapses (an indicator of memory formation). Further, even though the drug had a known half-life of only 15 minutes, elevated levels of BDNF and LTP were observed as long as 18 hours after drug administration was stopped.

Tiny RNA Molecules Fine-tune The Brain's Synapses (1/24/06)
Synapses between two neurons are formed between locations at the tip of an axon of one neuron (the "presynaptic" neuron) and a dendrite on the body of another neuron (the "postsynaptic" neuron). In order to form a complete synapse, it is necessary for there to be protrusions called "dendritic spines" on dendrites of the postsynaptic neuron. In the process of synaptic signaling, it is these spines that absorb neurotransmitter molecules released by the axon of the presynaptic neuron. Consequently, any mechanism that affects the density of spines on dendrites will affect the total number of synapses that can form between neurons.

It had previously been established that BDNF activates a protein kinase called Limk1, which in turn promotes the growth of dendritic spines and hence the ability of synapses to form. This research on rats studied the effect of the microRNA miR-134 on growth of dendritic spines of hippocampal neurons. It was found that when neurons were exposed to miR-134, spine volume significantly decreased, and synapses weakened. Conversely, when miR-134 was inhibited, spines increased in size, strengthening synapses. However, increased levels of BDNF negated the effects of miR-134, indicating that miR-134 achieved its effect by suppressing Limk1.

More: Spine control


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A couple of things about memory

Friday, March 21, 2008

First:

Children's Memory May Be More Reliable Than Adults' In Court Cases
Researchers Valerie Reyna, human development professor, and Chuck Brainerd, human development and law school professor--both from Cornell University--argue that like the two-headed Roman god Janus, memory is of two minds--that is, memories are captured and recorded separately and differently in two distinct parts of the mind.

They say children depend more heavily on a part of the mind that records, "what actually happened," while adults depend more on another part of the mind that records, "the meaning of what happened." As a result, they say, adults are more susceptible to false memories, which can be extremely problematic in court cases.

The implications of these results for legal testimony is not what I find especially interesting here. In fact, there are reasons why the testimony of children has sometimes been found to be less reliable than that of adults. Namely, in some cases, the techniques used to interview the children (before trial) have been improperly coercive or suggestive of particular interpretations.

What does seem interesting is the hypothesis that in adults memories of the same event tend to be stored in two distinct forms: literal details of "what happened", and interpretive judgments about the "meaning" of an event. But that in children it is primarily the actual details that are stored.
Reyna and Brainerd's Fuzzy Trace Theory hypothesizes that people store two types of experience records or memories: verbatim traces and gist traces.

Verbatim traces are memories of what actually happened. Gist traces are based on a person's understanding of what happened, or what the event meant to him or her. Gist traces stimulate false memories because they store impressions of what an event meant, which can be inconsistent with what actually happened.

The researchers have experimental evidence to support their conclusions. Some of this is noted in earlier accounts, such as this:

Children Less Prone To False Memories, Implications For Eyewitness Testimony, Study Shows
In a study published in the May issue of Psychological Science, Brainerd and Reyna presented a list of words for groups of first, fifth and ninth graders. Many of the words from this "study list" were related to each other (by belonging to certain categories such as animals, furniture, men's names) while others were unrelated "filler" words.

After a short break, the students were presented with a new "test list" composed of study list words, new words belonging to the aforementioned categories (animals, furniture, etc.), and distracter words that were new and entirely unrelated to the categories or the study list. Their task was to identify whether they had previously heard a word or not.

As predicted, if the test list provided a new word with a closely related meaning (a "semantic relation") to a word from the study list, older children were more likely to assert that they had heard it before. Simply put, the older children had more false memories in this case than younger children.

One can speculate about what's going on here. As people mature through childhood, they are constantly learning about the interrelationship of isolated details and events. (For instance, "Dad acts more scary after he's been drinking beer.") In addition, the accumulation of details makes more literal forms of memory cumbersome (and liable to confusion), so people learn to make abstractions and interpretations that summarize details and make storage easier by associating similar details in more general categories. However, this kind of fuzzy storage (or "fuzzy traces" as Brainerd and Reyna call it) can misrepresent the facts. (For instance, "Dad was drunk when he hit me" – which might not actually be true.)

Second, and not directly related to this, there are two quite indepentdent studies that show something about the relationship between memory and experience of stress.

The first item concerns observation of squirrels:

Correct Levels Of Stress Hormones Boost Learning, Squirrel Study Suggests
Tests on the influence that a stress-related hormone has on learning in ground squirrels could have an impact on understanding how it influences human learning, according to a University of Chicago researcher.

Jill Mateo, Assistant Professor in Comparative Human Development, has found that when they perform normal survival tasks, ground squirrels learn more quickly if they have a modest amount of cortisol, a hormone produced in response to stress, than those with either high or low levels of cortisol.

In humans, cortisol production is also related to stress and is known to have an impact on learning, but that impact is not well understood, Mateo said.

This should sound familiar to anyone who's been through even a few moderately difficult college courses. Namely, if the work in a particular course isn't difficult enough to cause at least a little stress, retention of the details may not be very complete. Without some stress, the material just doesn't seem "important" enough, even if it's new to the student, to compel the student's attention to the details and the complexity. But of course, if the material is difficult enough to cause excessive stress, anxiety can get in the way of successfully organizing the material in the student's mind.

The second study looked at the actual neurobiology of learning under conditions of acute stress:

Short-term Stress Can Affect Learning And Memory
Short-term stress lasting as little as a few hours can impair brain-cell communication in areas associated with learning and memory, University of California, Irvine researchers have found.

It has been known that severe stress lasting weeks or months can impair cell communication in the brain's learning and memory region, but this study provides the first evidence that short-term stress has the same effect.

As it turns out, another stress-related hormone besides cortisol is involved, corticotropin releasing hormone (CRH), and the latter is more significant under conditions of acute stress:
In their study, Baram and her UC Irvine colleagues identified a novel process by which stress caused these effects. They found that rather than involving the widely known stress hormone cortisol, which circulates throughout the body, acute stress activated selective molecules called corticotropin releasing hormones, which disrupted the process by which the brain collects and stores memories.

Learning and memory take place at synapses, which are junctions through which brain cells communicate. These synapses reside on specialized branchlike protrusions on neurons called dendritic spines.

In rat and mouse studies, Baram's group saw that the release of CRH in the hippocampus, the brain's primary learning and memory center, led to the rapid disintegration of these dendritic spines, which in turn limited the ability of synapses to collect and store memories.

The researchers discovered that blocking the CRH molecules' interaction with their receptor molecules eliminated stress damage to dendritic spines in the hippocampal cells involved with learning and memory.

The role of cortisol, in learning under conditions of moderate stress, remains somewhat less clear. In addition to the squirrel study, anecdotal experience with so-called "flashbulb memories" supports the idea that some degree of stress can assist the formation of memories. The Wikipedia article states, without references, "Some biologists believe that the hormone cortisol, which is released in response to stressful incidents, cooperate with epinephrine (adrenaline) to cause the formation of flashbulb memories by the brain, functioning to help remembering things to avoid in the future." The squirrel study suggests cortisol actually has some role in memory formation, rather than being just a coincidental byproduct of stress. (See also the article on Emotion and memory.

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Cheating

It's certainly appropriate – as well as hilarious – to draw the analogy between humans and slime molds. Kurt Vonnegut, Samuel Clemens, and H. L. Mencken would approve. But there's serious truth in it:

Some cheaters can keep it in their genes
A new study examining social behaviour suggests certain individuals are genetically programmed to cheat and often will do- providing they can get away with it.

The researchers looked at slime moulds - microscopic single-cell organisms or amoebae that are forced to cooperate with one another when food is in short supply. Studying slime moulds at the cellular level provides the scientists with a unique insight into the genes that may also influence human behaviour.

The international team, including biologists from The University of Manchester, found that some amoebae have the ability to use cheating tactics to give them a better chance of survival. The research - published in the journal Nature - not only demonstrates that cheating is a natural phenomenon governed by our genes but that it may be widespread among social creatures.

This is familiar territory. I wrote about it here, where the subject (among other things) was the evolutionary origins of altruism and cooperation. One needs to read that (or be familiar with the viewpoint of evolutionary psychology on the origins of morality and ethics) in order to see how the following speculations fit in.

Apparently, in many social species, there is a tendency for populations to evolve with an equilibrium mixture of cheaters and non-cheaters ("altruists"). Although cooperation increases the probability of group survival, some individuals in any group can gain an advantage by cheating, so they will tend to persist in groups as time goes on. But they can't become too numerous without harming the group's survival. So eventually some equilibrium is reached.

In the simulation of intergroup warfare I discussed in my earlier post, it was the warfare which worked against survival, so that under such conditions, there were pressures against a large equilibrium fraction of cheaters. These pressures were manifested in such things as religion and moral/ethical codes of behavior, together with formalized punishment of cheaters.

But warfare isn't the only factor that can put pressure on group survival. Simply living in a hostile or marginal environment can do it. This seems to be what happens with slime molds. Individuals can be, well, individualists until there is an existential threat.

One wonders whether this isn't what happened to the Neanderthals. Their environment was harsh. They must have migrated to that environment during favorable conditions (otherwise, why stay?), but eventually conditions got worse. If they were not able to evolve (biologically and/or socially) fast enough to reduce the percentage of cheaters, it's reasonable to suppose all would die. Modern humans living around the same time in similar environments – and who survived – perhaps were able to evolve faster. Or else they had already better capabilities for intragroup cooperation to deter cheating. Things like abilities in their brains for cheater detection, a "theory of mind", and ethical reasoning.

Other considerations suggest that worsening environmental conditions leads to more intergroup warfare (if population density is high enough, so that there is competition for resources, not merely strugle to survive, as on an island without competing groups). Such warfare would also promote cooperation and intragroup altruism over cheating.

What kind of cooperation is helpful in the non-warfare scenario? Sharing of resources (food, shelter, tools, clothing, etc.) Also communal support for raising orphaned children. Groups that had such customs and low proportions of cheaters would be more likely to survive at all.

Incidentally, one of the principal investigators (Chris Thompson) in the slime mold study, seems to know his subject pretty well. Here's another item about his slime mold research.

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Embryonic stem cells and Klf4

Monday, March 17, 2008

There's now some additional information on one of the transcription factors written about here, which are able to reprogram adult skin cells into embryonic stem cells. To review, one of the teams responsible for this research used Oct3/4, Sox2, c-Myc, and Klf4 for the reprogramming, while another team used Oct3/4, Sox2, Nanog and Lin28.

Of the transcription factors in the first list, all but Klf4 have been well-studied. So it is of some interest to know more about Klf4, and why it seems to be somewhat less essential than the others.

Some of the interesting details are reported on here: Molecular Alliance That Sustains Embryonic Stem Cell State Identified.

Klf4 is normally active in real embryonic stem cells. To investigate the role Klf4 might be playing in the reprogramming of skin cells, the researchers investigated embryonic stem cells that had been artificially depleted of Klf4. To their surprise, the team found that the cells maintained their pluripotency.

The question then was how to explain this. What was found is that two closely-related transcription factors – Klf2 and Klf5 – took over the role of Klf4:
"Most important, the data showed that the other Klfs were bound to the target sites when one of them was depleted." said Dr. Ng. "These Krüppel-like factors form a very powerful alliance that work together on regulating common targets. The impact of losing one of them is masked by the other two sibling molecules."

This family of transcription factors, called Kruppel-like factors, gets its name from a homology to the Drosophila Krüppel protein. Members of this family have been studied for their roles in cell proliferation, differentiation and survival, especially in the context of cancer.

Interestingly enough, according to the research press release,
Klfs were found to regulate the Nanog gene and other key genes that must be active for ES cells to be pluripotent, or capable of differentiating into virtually any type of cells. Nanog gene is one of the key pluripotency genes in ES cells.

"We suggest that Nanog and other genes are key effectors for the biological functions of the Klfs in ES cells," Dr. Ng said.

"Together, our study provides new insight into how the core Klf circuitry integrates into the Nanog transcriptional network to specify gene expression unique to ES cells.

Nanog, of course, is one of the transcription factors in the set of transcription factors which was found to be an alternative, for reprogramming adult cells, to the set that contained Klf4.

The Nanog protein, too, is known to be critically important in pluripotent stem cells. It is a homeobox transcription factor that appears to play an essential role in self-renewal of undifferentiated embryonic stem cells. It also appears to be connected with cancer, because (according to Wikipedia) "It has been shown that the tumour suppressor p53 binds to the promoter of NANOG and suppresses its expression after DNA damage in mouse embryonic stem cells. p53 can thus induce differentiation of embronic stem cells into other cell types which undergo efficient p53-dependent cell-cycle arrest and apoptosis."

The connection of Klf proteins with cancer is not only through Nanog. According to Wikipedia, "Klf4 also interacts with the p300/CBP transcription co-activators." The closely-related p300 and CBP "interact with numerous transcription factors and act to increase the expression of their target genes." And they too are involved with cancer:
Mutations in the p300 gene have been identified in several other types of cancer. These mutations are somatic, which means they are acquired during a person's lifetime and are present only in certain cells. Somatic mutations in the p300 gene have been found in a small number of solid tumors, including cancers of the colon and rectum, stomach, breast and pancreas. Studies suggest that p300 mutations may also play a role in the development of some prostate cancers, and could help predict whether these tumors will increase in size or spread to other parts of the body. In cancer cells, p300 mutations prevent the gene from producing any functional protein. Without p300, cells cannot effectively restrain growth and division, which can allow cancerous tumors to form.

Another intriguing connection of p300 is that it can be inhibited by the action of the sirtuin deacetylase Sirt1. (See here.)

P300/CBP themselves are targets of intense research activity. Their physical structure has only very recently been determined. (See here, here, here.)

Finally (for now), it's interesting that p300 plays a role in stem cell signaling through one of our favorite signaling pathways – Wnt (see here). According to this report: Stem Cell Signaling Mystery Solved, a small molecule called IQ-1 interferes with Wnt signaling via p300:
What IQ-1 does, Kahn explains, is to block one arm of a cell-signaling pathway called the Wnt pathway, while enhancing the signal coming from the other arm of the Wnt pathway. The Wnt pathway is known to have dichotomous effects on stem cells i.e. both proliferative and differentiative. More specifically, IQ-1 blocks the coactivator p300 from interacting with the protein ß-catenin; this prevents the stem cells from being 'told' to differentiate into a more specific cell type.


Additional reading:

A core Klf circuitry regulates self-renewal of embryonic stem cells – research abstract published online 2/10/08

Molecular Alliance Identified that Sustains Embryonic Stem-Cell State – another summary of the Klf4 study

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MicroRNA and stem cells

Sunday, March 16, 2008

I've written about both microRNA and stem cells recently. But there is more news that reports on connections between the two.

Following are summaries of the announcements.

Role Of Tiny RNAs In Controlling Stem Cell Fate Identified (3/6/08)
The microRNAs miR-1 and miR-133 have been known to be associated with muscle development. The new research shows that they actively encourage heart muscle development and suppress genes that could cause pluripotent embryonic stem cells to turn into undesired cells like neurons or bone. The two miRNAs turn on genes that encourage mesoderm formation. They also turn off genes that cause stem cells to become ectodermal or endodermal cells.

Research abstract: MicroRNA Regulation of Cell Lineages in Mouse and Human Embryonic Stem Cells.
Blog post: here.

Short RNA Strand Helps Exposed Skin Cells Protect Body From Bacteria, Dehydration And Even Cancer (3/2/08)
In a wide range of vertebrates, from zebrafish to chickens and humans, miR-203 is found only in very specific types of skin – the outer layers of stratified epithelial tissues. In the 13th day of mouse embryo development, the embryo's skin is primarily composed of undifferentiated stem cells, and there is very little miR-203 in the cells. During the next two days expression of miR-203 rises rapidly, and the cells begin to differentiate into cells that form the outermost, protective layer of skin.

When miR-203 was artificially caused to be expressed too early, the normal rapid proliferation of stem cells was significantly slowed. The effect was attributed to inhibition of the p63 gene, which normally encourages stem cell proliferation, by miR-203. On the other hand, when miR-203 was suppressed, cells in the outer layer proliferated significantly more than normally, because p63 was not being inhibited.

p63 is a master regulatory gene, which maintains pluripotency in skin stem cells. It is often found to be overexpressed in cancerous cells. Future research will explore whether low expression of miR-203 is associated with cancer, and if so, whether increasing miR-203 expression is helpful.

More: here.

MicroRNA Pathway Essential For Controlling Self-renewal Of Stem Cells (2/15/07)
The gene Dicer-1 (Dcr-1) has been known to affect expression of specific miRNAs in fruit flies (Drosophila). It is essential for generating mature miRNAs from their corresponding precursors. This research shows that unmutated Dcr-1 is necessary for controlling self-renewal or maintenance of germline stem cells and somatic stem cells in Drosophila ovaries. The researchers infer that lack of miRNAs, due to mutant Dcr-1, is responsible for failure of self-renewal of stem cells, but specific miRNAs that are affected are yet to be determined.

Research abstract: Dcr-1 Maintains Drosophila Ovarian Stem Cells.
Blog post: here.


Additional reading:

  • MicroRNA-134 Modulates the Differentiation of Mouse Embryonic Stem Cells, Where It Causes Post-Transcriptional Attenuation of Nanog and LRH1 – abstract of research paper published online 10/4/07

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  • Alternative energy sources

    Saturday, March 15, 2008

    The outlook on energy alternatives to fossil fuels is looking a little bleak.

    There have been several recent studies or reports casting significant doubt on the economic and/or environmental viability, at least for the near and intermediate future, of some of the leading contenders to supplant fossil fuels.

    First up: nuclear power. Of course, environmentalists and others have had grave doubts about nuclear for decades, because of problems with safe disposal of spent nuclear fuel and the dangers of diversion of enriched uranium to manufacture of weapons. On top of that, there is the argument that replacing generation of power from burning fossil fuels with generation from nuclear sources may well contribute more to release of CO2 into the atmosphere than continuing to use fossil fuels. This comes about because so much power (generated from burning of fossil fuels) will need to be expended simply to build from scratch many new nuclear power plants and sharply increase the mining and purification of uranium:

    Nuclear Power Not Efficient Enough To Replace Fossil Fuels, Study Finds
    Nuclear energy production must increase by more than 10 percent each year from 2010 to 2050 to meet all future energy demands and replace fossil fuels, but this is an unsustainable prospect. According to a report published in Inderscience's International Journal of Nuclear Governance, Economy and Ecology such a large growth rate will require a major improvement in nuclear power efficiency otherwise each new power plant will simply cannibalize the energy produced by earlier nuclear power plants.

    Here's another way to look at this. If you consider just the marginal costs of producing a kW of energy from nuclear fuel vs. fossil fuel – counting (if you can) both direct economic costs and costs due to release of CO2 into the atmosphere – nuclear energy might be superior. However, if you also consider the capital expense (both direct and indirect) required to build enough new nuclear facilities to replace existing conventional facilities and also meet increased demand, then (according to the study) nuclear loses.

    So what about using other energy sources as alternatives to fossil fuels, in order to significantly reduce dependency on fossil fuels and release of CO2? Like hydrogen, for example. Of course, this depends on further developing a lot of technology that's either not cost-competitive yet (fuel cells) or not even available yet (practical and safe means of storing and transporting hydrogen). To say nothing of the capital costs (as above) needed to build hydrogen infrastructure if and when the technology is available.

    Even if technology can solve the difficult problems of storing and transporting hydrogen, there's another fundamental problem. Hydrogen itself is more of a form of energy suitable for transport and storage than it is a readily available source of energy (like sunlight or fossil fuels) that can be acquired or extracted (relatively) cheaply. There's no hydrogen just sitting around (like natural gas) waiting to be mined and distributed. Energy has to be consumed in order to separate hydrogen from oxygen, which together make up H2O. This energy has to come from some other source, as input to the electrical/chemical process that separates out hydrogen (or recombines it to make another fuel such as methane). This energy is regained later – but always with some percentage loss – when hydrogen is chemically recombined with oxygen (as in a fuel cell).

    There really isn't any energy advantage to hydrogen at all, except for the (presumed) advantage over batteries in storage and transport. Of course, energy in a storable form is required for use in vehicles like cars and airplanes, in spite of the unavoidable losses along the way. The following essay goes into all of this in more detail.

    The Hydrogen Economy
    Skeptics scoff at perpetual motion, free energy, and cold fusion, but what about energy from hydrogen? Before we invest trillions of dollars in a hydrogen economy, we should examine the science and pseudoscience behind the hydrogen hype.

    There are some problems with the essay. First, one does not "make" hydrogen. It is extracted from chemical compounds like water, hydrocarbons (fossil fuels except coal), or biomass (carbohydrates, cellulose, etc.). Energy has to be input to the process in order to break the chemical bonds between hydrogen and other elements (carbon or oxygen). You get the energy back out when hydrogen recombines with oxygen or carbon (in a fuel cell, combustion chamber, etc.) – but always at some loss.

    Second, the essay mostly assumes hydrogen will be stored and transported in liquid form, which is difficult and expensive, since liquid hydrogen boils at an ultracold -253°C. There is some hope that technology can be developed to store gaseous hydrogen in exotic solid materials at reasonable temperatures and pressures. (Recent examples: here, here.) However, at this point that's still conjectural. The larger point is that a practical "hydrogen economy" is still, at best, not in the near future.

    So hydrogen is not an energy source, and it is even very problematical as a way to store energy in a portable form for use in cars and airplanes. Fortunately, there are other ways to make energy portable, such as batteries. A Toyota Prius uses nickel metal hydride batteries to store energy from the regenerative braking system, and it seems to be an economically successful product. Lithium ion batteries, such as are used in laptop computers, have a higher energy density than the nickel metal hydride type. They have problems of their own, but significant improvements are being made. (See here, here, here.)

    That still leaves the problem of developing additional actual sources of energy, that are alternatives to fossil fuels. Ethanol (grain alcohol) is getting a lot of publicity these days. It's politically popular with the agricultural industry, for obvious reasons. Ethanol partially solves one problem with fossil hydrocarbon fuels – by removing some dependence on politically unstable areas as a fuel source. But ethanol does nothing for the problem of CO2 emissions.

    And it creates serious problems of its own, such as driving up the cost of agricultural products needed to feed people. Further, as with hydrogen, it takes a lot of energy to extract ethanol (or other energy carriers such as other biofuels or methane) from agricultural crops or biomass. Critiques of ethanol and other biofuels are not new, though they don't seem to get the attention they deserve. (See here, here, here, for example.)

    Other alternatives? There's always solar (photovoltaic) energy. Of all new but currently available alternative energy sources to fossil fuels (whether oil, natural gas, or coal), solar seems to be the most economical, especially taking reduced CO2 emissions into account.

    But of course, solar also has its problems too. These include capital costs for building infrastructure to capture solar energy and to store it (for peak or nighttime use) or transmit it from the sunniest areas with low land prices. It's these capital costs (initial construction and eventual replacement) that hurt, since the marginal cost of each kWh is almost nil.

    However, making detailed economic comparisons with traditional energy sources is rather difficult, as this study argues: Cloudy Outlook For Solar Panels: Costs Substantially Eclipse Benefits.

    It would seem that the real difficulty of economic analysis lies in predicting the future costs of conventional energy sources – fossil fuels, especially oil. Some of the problems:

    • How to estimate costs associated with CO2 emissions, given that the idea of global warming itself is so controversial (especially in the minds of economists and political officials, if not atmospheric scientists). To say nothing of estimating social costs of conjectural side effects, such as sea level rise, serious water shortages, detrimental impact on human and animal health, impact on agricultural production, etc.
    • How to estimate the foreseeable rise in price of fossil fuels (especially oil) due to political instability, rising extraction costs (deep ocean sources), depletion of supplies, and rapid increase in demand from developing parts of the world. (There are large uncertainties in all of these factors, and some cost has to be allocated to this uncertainty itself.)
    • How to handle the issue of proper pricing for energy at times of peak demand, as opposed to off-hours. (The report just mentioned discusses this.)

    At present, the cost of solar energy, taking into account such things as installation costs, depreciation, etc., might well be two to four times the cost of energy from fossil fuels. But at least the cost of solar is pretty certain to decline, while the cost of energy from fossil fuels can only increase – and at a worrisomely unpredictable rate, in view of the uncertainties just listed.

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    Induced pluripotent stem cells

    Friday, March 7, 2008

    It was one of the top science stories of 2007: number 2 on Science's list – reprogramming ordinary adult body cells (of mice and humans) to act like embryonic stem cells. (See here for summary.) As Science put it,
    The riddle of Dolly the Sheep has puzzled biologists for more than a decade: What is it about the oocyte that rejuvenates the nucleus of a differentiated cell, prompting the genome to return to the embryonic state and form a new individual? This year, scientists came closer to solving that riddle. In a series of papers, researchers showed that by adding just a handful of genes to skin cells, they could reprogram those cells to look and act like embryonic stem (ES) cells.

    The story really began in October 2006, when a team at Kyoto University in Japan, led by Shinya Yamanaka, announced that they had reprogrammed mouse skin cells into cells that closely resembled embryonic stem cells, based on certain characteristic genes that were expressed. The reprogramming was done by introducing genes for four important stem cell transcription factors (Oct4 (or sometimes the similar Oct3), Sox2, c-Myc, and Klf4) into the skin cells with the help of a genetically engineered retrovirus. (See here for more about Oct4.)

    But the team could not at that time demonstrate that these reprogrammed cells would differentiate into a variety of adult cells after having been introduced into a mouse embryo which then developed into an adult mouse. Being able to do this would verify the pluripotency of the reprogrammed cells. (Pluripotency is the ability of a cell to develop into any type of fetal or adult cell. It is characteristic of embryonic stem cells.) The reprogrammed cells are called induced pluripotent stem (iPS) cells.

    However, in June 2007 Yamanaka's team, along with two others, reported that they had been able to provide the missing demonstration of pluripotency. The second team that joined in reporting this accomplishment was led by Rudolf Jaenisch at MIT's Whitehead Institute for Biomedical Research. The third team was led jointly by Konrad Hochedlinger of the Harvard Stem Cell Institute and Kathrin Plath of the UCLA Institute for Stem Cell Biology and Medicine. (References: here, here, here, here, here, here, here, here, here.)

    The crucial step, of course, was being able to reprogram adult human cells in the same way. For all anyone knew, this might be quite difficult. However, just five months later, in November 2007, Yamanaka's team, together with another led by James Thomson of the University of Wisconsin, announced that this objective had been accomplished. (References: here, here, here, here, here, here, here, here, here, here.)

    Yamanaka's team used the same four transcription factors for the human cells as they used for the mouse cells. The cells they reprogrammed were adult human fibroblasts. Thomson's team also used Sox2 and Oct3/4, but instead of c-Myc and Klf4 they used other transcription factors: Nanog and Lin28. The cells they reprogrammed were fetal or newborn fibroblasts.

    Very soon thereafter, the Japanese team announced that they could also dispense with c-Myc. That was good, because c-Myc is linked with cancer, as we discussed here. But the downside was that the process was much slower and less efficient. (References: here, here.)

    In early December the Jaenisch tean from the Whitehead Institute collaborated with a team led by Tim Townes of the University of Alabama to show that their mouse iPS cells could treat a mouse model of sickle cell anemia. Specifically, they started with skin cells from sickle cell mice and made iPS cells. They also added a corrected hemoglobin gene, and then let the cells differentiate into blood-producing stem cells. When these cells were placed in mice whose defective blood stem cells had been killed, healthy red blood cells were eventually produced, alleviating the symptoms of sickle cell disease. (References: here, here, here, here, here, here, here.)

    Of course, it's far too early to attempt such an experiment with humans. All concerns about the possiblity of cancer developing from the iPS cells would need to be cleared away. Then the procedure would need to be tested carefully using a lengthy series of clinical trials.

    In late December, a team led by George Daley from Harvard Medical School and Children's Hospital in Boston announced thay they had also been able to convert ordinary human skin cells into embryonic-like stem cells. (See here.) The team had also programmed iPS cells from mesenchymal stem cells (adult stem cells found in bone marrow that can differentiate into fat, bone and cartilage).

    Recently (mid-February), Kathrin Plath's team at UCLA has also announced success in reprogramming human skin cells, using the same techniques as previously reported. They have also verified that the induced pluripotent cells are very similar to embryonic stem cells:

    Human Skin Cells Reprogrammed Into Embryonic Stem Cells (2/11/08)
    The reprogrammed cells were not just functionally identical to embryonic stem cells. They also had identical biological structure, expressed the same genes and could be coaxed into giving rise to the same cell types as human embryonic stem cells.

    As we've noted, there have been some potential problems with the work already mentioned. First, any process that activates c-Myc (directly or indirectly) runs risks of promoting cancerous tumors. Second, the processes have used retroviruses to introduce the necessary genetic material into cells to be reprogrammed. This also runs the risk of inducing cancer.

    So Konrad Hochedlinger's team has come along with work in mice to reduce or remove these cancer-causing risks:

    Discovery Could Help Reprogram Adult Cells To Embryonic Stem Cell-like State (2/15/08)
    Harvard Stem Cell Institute (HSCI) and Massachusetts General Hospital (MGH) researchers have taken a major step toward eventually being able to reprogram adult cells to an embryonic stem cell-like state without the use of viruses or cancer-causing genes.

    In a paper released online today by the journal Cell Stem Cell, Konrad Hochedlinger and colleagues report that they have discovered how long adult cells need to be exposed to reprogramming factors before they convert to an embryonic-like state, and have “defined the sequence of events that occur during reprogramming.”

    This work on adult mouse skin cells should help researchers narrow the field of candidate chemicals and proteins that might be used to safely turn these processes on and off. This is particularly important because at this stage in the study of these induced pluripotent (iPS) cells, researchers are using cancer-causing genes to initiate the process, and are using retroviruses, which can activate cancer genes, to insert the genes into the target cells. As long as the work involves the use of either oncogenes or retroviruses, it would not be possible to use these converted cells in patients.

    And hard on their heels, other teams are announcing similar findings:

    Stem cell breakthrough may reduce cancer risk (2/27/08)
    The main obstacle to using "reprogrammed" human stem cells – the danger that they might turn cancerous – has been solved, claims a US company.

    PrimeGen, based in Irvine, California, says that its scientists have converted specialised adult human cells back to a seemingly embryonic state – using methods that are much less likely to trigger cancer than those deployed previously.

    The company also claims to be able to produce reprogrammed cells faster and much more efficiently than other scientists.

    More: here.

    Additional reading:


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    Satellite Catches a Galaxy Ablaze With Starbirth

    Monday, March 3, 2008

    NASA's Swift Satellite Catches a Galaxy Ablaze With Starbirth (2/26/08)
    The Triangulum Galaxy is also called M33 for being the 33rd object in Charles Messier’s sky catalog. It is located about 2.9 million light-years from Earth in the constellation Triangulum. It is a member of our Local Group, the small cluster of galaxies that includes our Milky Way Galaxy and the Andromeda Galaxy (M31). Despite sharing our Milky Way’s spiral shape, M33 has only about one-tenth the mass. M33’s visible disk is about 50,000 light-years across, half the diameter of our galaxy.

    Swift’s Ultraviolet/Optical Telescope (UVOT) took the images through three separate ultraviolet filters from December 23, 2007 to January 4, 2008. The mosaic showcases UVOT’s high spatial resolution. Individual star clusters and star-forming gas clouds are clearly resolved, even in the crowded nucleus of the galaxy. The image also includes Milky Way foreground stars and much more distant galaxies shining through M33.




    M33 – click for 1440× 900 image


    More: here, here, here

    Exascale computing

    Saturday, March 1, 2008

    I don't have a whole lot new to say on this topic right now. Earlier comments are here. To recap, "petascale" refers to computers capable of doing 1015 arithmetic operations ("flops") per second. Such computers already exist. The next main step is "exascale" – computers 1000 times as fast, capable of doing 1018 operations per second. Such computers don't exist yet – but people are already starting to work towards this goal.

    One Million Trillion 'Flops' Per Second Targeted
    Preparing groundwork for an exascale computer is the mission of the new Institute for Advanced Architectures, launched jointly at Sandia and Oak Ridge national laboratories. ...

    The idea behind the institute —under consideration for a year and a half prior to its opening — is “to close critical gaps between theoretical peak performance and actual performance on current supercomputers,” says Sandia project lead Sudip Dosanjh. “We believe this can be done by developing novel and innovative computer architectures.”

    Ultrafast supercomputers improve detection of real-world conditions by helping researchers more closely examine the interactions of larger numbers of particles over time periods divided into smaller segments.


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