Memory and BDNF

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

                                                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

                                                  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

                                                       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

                               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 about alternative energy

About a month ago, I wrote about the shortcomings of various alternative energy sources. That was mainly about a variety of problems with nuclear energy, solar energy (photovoltaics), and hydrogen.

I didn't even get into the subject of biofuels, but I should have, because the problems in that area are becoming painfully obvious.

Ordinarily I would not expect to find much significant reporting on a scientific/technical subject in Time magazine, especially something that challenges "conventional wisdom". But via DarkSyde at Kos I see there's an interesting article on the problems of "biofuel": The Clean Energy Scam

Several new studies show the biofuel boom is doing exactly the opposite of what its proponents intended: it's dramatically accelerating global warming, imperiling the planet in the name of saving it. Corn ethanol, always environmentally suspect, turns out to be environmentally disastrous. Even cellulosic ethanol made from switchgrass, which has been promoted by eco-activists and eco-investors as well as by President Bush as the fuel of the future, looks less green than oil-derived gasoline.

Meanwhile, by diverting grain and oilseed crops from dinner plates to fuel tanks, biofuels are jacking up world food prices and endangering the hungry.

The Time article focuses on the loss of rainforest, and consequently the loss of its ability to soak up and sequester CO2. When the forest is gone, CO2 will still be incorporated in biomass (crops of some sort). But then that is converted to biofuel, and released back into the atmosphere when it's burned. (To say nothing of the energy that's just wasted along with release of CO2 when the forest biomass is burned to clear it away.) Given all the energy that has to be expended to grow and harvest biofuel crops, with resulting additional release of CO2, we are worse off in terms of greenhouse gas emissions than if we just burned oil (or even coal).

But that's not the only serious problem. Crops that are grown to make fuel (from sugar cane, corn, switchgrass, or whatever) use land where food crops (for people and animals) could be grown instead. Driving up the cost of food for everyone on the planet. (Have you checked the price of bread or eggs at the market recently?)

Economists have spoken out about this problem for several years, when the hype for biofuels and ethanol was just beginning to build. For instance, we have from Howard Simons in early 2006: Making Our Food Fuel Isn't the Answer

If high prices strengthen energy's claim on food supplies, governments everywhere will intervene on behalf of their hungry citizens. If low prices torpedo biofuels' economics, governments everywhere will respond with subsidies for these industries. Only an elimination of current mandates and subsidies today will avoid these problems tomorrow, but the likelihood of this happening is near zero. Somehow I believe we will rue the day when we decided to make food and fuel substitutes at the margin.

In early 2007 Paul Krugman picked up the story: The Sum of All Ears

There is a place for ethanol in the world’s energy future — but that place is in the tropics. Brazil has managed to replace a lot of its gasoline consumption with ethanol. But Brazil’s ethanol comes from sugar cane.

In the United States, ethanol comes overwhelmingly from corn, a much less suitable raw material. In fact, corn is such a poor source of ethanol that researchers at the University of Minnesota estimate that converting the entire U.S. corn crop — the sum of all our ears — into ethanol would replace only 12 percent of our gasoline consumption.

So ethanol doesn't even help the U. S. all that much in terms of dependence on foreign oil. And this February Krugman returned to the subject here, linking to this: Ethanol Demand in U.S. Adds to Food, Fertilizer Costs

About 33 percent of U.S. corn will be used for fuel during the next decade, up from 11 percent in 2002, the Agriculture Department estimates. Corn rose 20 percent to a record on the Chicago Board of Trade since Dec. 19, the day President George W. Bush signed a law requiring a fivefold jump in renewable fuels by 2022.

Increased demand for the grain helped boost food prices by 4.9 percent last year, the most since 1990, and will reduce global inventories of corn to the lowest in 24 years, government data show. While advocates say ethanol is cleaner than gasoline, a Princeton University study this month said it causes more environmental harm than fossil fuels.

And then last week Krugman had even more: Grains Gone Wild

The subsidized conversion of crops into fuel was supposed to promote energy independence and help limit global warming. But this promise was, as Time magazine bluntly put it, a “scam.”

This is especially true of corn ethanol: even on optimistic estimates, producing a gallon of ethanol from corn uses most of the energy the gallon contains. But it turns out that even seemingly “good” biofuel policies, like Brazil’s use of ethanol from sugar cane, accelerate the pace of climate change by promoting deforestation.

And meanwhile, land used to grow biofuel feedstock is land not available to grow food, so subsidies to biofuels are a major factor in the food crisis. You might put it this way: people are starving in Africa so that American politicians can court votes in farm states.

Here's a report of a scientific study on the issue: Some Biofuels Risk Biodiversity And Could End Up Harming Environment

Corn-based ethanol is currently the most widely used biofuel in the United States, but it is also the most environmentally damaging among crop-based energy sources.

Finally, to bring this back to a solid scientific foundation, Sean at Cosmic Variance reminds us that Energy Doesn’t Grow on Trees

In particular, biofuels (such as ethanol) and hydrogen are not actually sources of energy — given the vagaries of thermodynamics, it costs more energy to create them than we can get by actually using them, as there will inevitably be some waste heat and entropy produced
.

Although all this bad news about just about every prospective near-term form of alternative energy is discouraging, there are a few other options that may become available in the slightly more distant future. There's the old perennial, controlled nuclear fusion. Even though work on that is even more active than ever, it's still at least several decades away.

But there's another significant option that's often overlooked: solar power satellites. This technology uses very large arrays of photovoltaic panels high in orbit around the earth. The energy is beamed back to the ground in the form of microwaves. (So this should not be confused with simply using mirrors to redirect additional sunlight, which presents serious problems of its own.)

Solar power satellites also have many uncertainties and potential problems, but the largest is simply boosting enough of them into orbit, and maintaining them. A possible approach to those problems involves space elevators. But those, again, present a whole additional set of challenges.

For now, here are a couple of articles from last fall with more details:

Consciousness, free will, etc.

For quite a long time, the subject of "consciousness" was not considered especially suitable for scientific investigation. A tremendous amount has been written about it, of course. But most of that has been written by philosophers rather than working scientists. Quite a few, if not a substantial majority, of philosophers seem to think that consciousness is a "mystery" that isn't likely to be understood scientifically anytime soon, if ever.

Well, on one hand, when a subject is not very amenable to scientific investigation, then it usually is philosophers, rather than scientists, who write and speak about it. Only when you see that situation change, and you have actual experimental scientists working on the problem and having the technology to actually conduct meaningful experiments, is it time to regard the subject as fair game for science.

At one time even physics was a subject discussed more by philosophers than by scientists. But that changed when people like Galileo and Newton came along, followed by many others. In regard to consciousness, perhaps the technology known as "functional MRI" may be the factor that tips the scales towards real science.

On the other hand, my general opinion of philosophers is well expressed by a quote attributed to one of the all time greatest scientists, C. F. Gauss: "When a philosopher says something that is true, then it is trivial. When he says something that is not trivial, then it is false."

However that may be, we are now in fact seeing real scientific work being done on the subject of consciousness. It's a vast field, I can only scratch the surface here, and I won't go into much detail about any of this. But perhaps a good example of relevant recent research on consciousness is this:

Brain scanner predicts your future moves

                          Long before you decided to read this story, your brain may have already said "click that link".

By scanning the brains of test subjects as they pressed one button or another – though not a computer mouse – researchers pinpointed a signal that divulged the decision about seven seconds before people ever realised their choice. The discovery has implications for mind-reading, and the nature of free will.

Seven seconds. Think about that for a bit. Where, exactly, is "free will", if the brain has already made, or almost made, a decision seven seconds before one is even conscious of a decision having been made?

Sure, one can argue that "free will" comes into play near the final stage of the process, when a course of action is consciously considered before commitment is made to it. Perhaps. But consider something like drug addiction. Just how much "free will" does an addict actually have to resist his/her cravings? Rather little, no? There's quite a bit of research into addiction now, and it is supporting the idea that addictive behavior is largely driven by brain chemistry. I could cite dozens of recent reports in this area, but I need to move on to other stuff right now. Maybe more on addiction later.

Oh yes, and there are a number of other brain states that appear to significantly affect behavior much more strongly than does conscious deliberation. States such as pain, extreme hunger or thirst, the experience of being tortured by agents of the U. S. government, etc.

There's another area of research that comes to mind in connection with significant unconscious influences on people's thoughts and behavior. Psychologists have a term for it: "priming". What it means is that one can manipulate, at least on a statistical basis, the behavior of another person, such as an experimental subject, a voter, or a "consumer", by subtly exposing the subject to various kinds of cues before eliciting the behavior to be manipulated. The subject may be consciously aware of the cues, but not of how they affect subsequent behavior.

Again, I could probably come up with many examples of studies on this if I had more time. Maybe later. Just two examples now, this story that appeared last year: Who’s Minding the Mind?. I wrote about that here, along with another, somewhat older story (A New Study Suggests A Relationship Between Fear Of Death And Political Preferences). Something to think about in this election year.

Moving right along, this all sets the stage for the following very recent report:

Blind to Change, Even as It Stares Us in the Face
                                             The phenomenon that Dr. Wolfe’s Pop Art quiz exemplified is known as change blindness: the frequent inability of our visual system to detect alterations to something staring us straight in the face. The changes needn’t be as modest as a switching of paint chips. At the same meeting, held at the Italian Academy for Advanced Studies in America at Columbia University, the audience failed to notice entire stories disappearing from buildings, or the fact that one poor chicken in a field of dancing cartoon hens had suddenly exploded. In an interview, Dr. Wolfe also recalled a series of experiments in which pedestrians giving directions to a Cornell researcher posing as a lost tourist didn’t notice when, midway through the exchange, the sham tourist was replaced by another person altogether.

The article is a report by Natalie Angier on research into consciousness and attention by neuroscientist Jeremy Wolfe. I won't attempt to say much about it, except that it concerns the interplay of consciousness and attention. And how in some sense we are not really conscious of as much as we think we are. The sense data are streaming into our brains, and they do register at some level that appears to be conscious. But in fact, only a part of the information stream that is the focus of "attention" actually seems to matter." Attention" is the brain's mechanism for limiting actual processing to just a part of the data stream that, somehow, seems most important.

I won't attempt to summarize more than that. Angier is a pretty good writer. Read the article for yourself. Actually, speaking of Angier, I should remark that I have expressed reservations before about her writing style (here). There I described her style as "too flowery and gaudy for my taste". The article mentioned above is fairly tame in that regard. But sometimes what she writes seems, to me anyhow, to be best described as somewhat twee.

Now, "twee" is a word you may not be familiar with if you have been exposed mainly to U. S. English (and you don't do crossword puzzles). It's a British word. A rough American equivalent might be "affected". However, I used "twee" to make a point. Namely, that if you didn't know the meaning, but you looked it up, I'm pretty sure you won't have much trouble remembering it. Why? Because I brought it to your attention.

So you see, although you were probably conscious of the word when you read it, having had your attention focused on it will tend to be the catalyst that gets it added to your memory.

The brain has other mechanisms for directing consciousness in certain ways and for raising the probability that certain kinds of data get remembered. Emotion is one such psychological mechanism that has this effect. I've touched on this tangentially when I wrote about stress and memory here. Also think about "flashbulb memories".

The point is that sensory data that is accompanied by significant emotional valence tends to be preferentially stored in memory. Various hormones and growth factors (such as BDNF) seem to play a role in this process. Consciousness per se... not so much. You have been conscious of quite a lot that you have already forgotten the next day (such as, perhaps, what you had for breakfast a day or two ago).

Here's another report of recent research that tends in the same direction. It concerns the role of emotion in the sense of smell, and which olfactory experiences tend to be stored in memory:

One Bad Experience Linked To Sniffing Out The Danger

                                             Each human nose encounters hundreds of thousands of scents in its daily travels perched front and center on our face. Some of these smells are nearly identical, so how do we learn to tell the critical ones apart?

Something bad has to happen. Then the nose becomes a very quick learner.

New research from Northwestern University's Feinberg School of Medicine shows a single negative experience linked to an odor rapidly teaches us to identify that odor and discriminate it from similar ones.

I don't think I need to comment further on that, with respect to how the emotional circuitry of the brain influences the memory storage circuitry.

Time to wrap up now. I'm going to indulge in a bit of anecdotal reporting on a few of my own observations on consciousness. This is just speculation on my part, not scientific data at all, of course. Think about your own experiences and see whether they aren't consistent with the possibility that consciousness is just another brain mechanism, which serves various purposes, and interacts in different ways with other brain mechanisms. If this is so, eventually we should be able to understand scientifically what the biology of consciousness is.

First off, I'll note that I recently had a colonoscopy. (Nothing bad found. Thanks for asking.) The most interesting part of the experience was how readily consciousness can be turned on and off. Before the procedure began, I was injected with two drugs: Demerol and Versed. The former blocks pain. The latter is a strong sedative that basically turns off consciousness for a brief, fairly predictable period of time.

For a couple of minutes after receiving the Versed, I didn't notice anything unusual, no drowsiness, no disorientation, nada. I just looked around and noticed various features of the immediate environment, such as the staff and the monitoring instruments. I can still picture that stuff fairly clearly. Of the next half hour or so while the procedure was going on, I can recall nothing at all. And then I was awake again, and everything seemed pretty normal. I can recall that period clearly too.

What I conclude from this is that consciousness and memory formation are both processes and/or mechanisms that can be turned off pretty mechanically with a simple chemical. Probably the memory formation is turned off first, so that the intermediate state of drowsiness (if it even occurred) was not remembered. And then as soon as the chemical has been metabolized away, consciousness and memory formation resume with little aftereffect. (Physicians maintain that a patient's judgment can be compromised for several hours afterwards. Perhaps so, but I could detect little evidence of that.) I was also told that patients under the effects of the drugs are still consciousness enough to follow verbal instructions. But of course, I have no memory of whether this is true.

This experience was not like falling asleep normally, when there is usually a definite period of drowsiness that one can often remember the next day. Nevertheless, once asleep one is no longer conscious in the usual sense. Again this suggests that consciousness is just a mechanism that can be turned off (though not by means of volition, unfortunately) at appropriate times.

But we all realize that many mental processes do not cease when we are asleep. For instance, perceptual data is still coming in and processed by the brain to some extent. Noises, especially, that can and do wake us up. Then there is dreaming, which seems to engage large parts of the machinery of consciousness, including emotional subsubsystems (fear and pleasure), and perceptual processing systems of vision and hearing – only on internally generated rather than external sensory data. Sometimes external perceptual data becomes part of the dream consciousness, but usually not.

Another interesting aspect of dreaming is how it interacts with memory. We all know how quickly, after we wake up, we forget about what we may have been dreaming. This suggests that the short term memory system has been functioning, but loses its content more or less as usual. Intermediate and long term memory systems seem to be shut down. It's very unusual (in my experience) to remember any dreams several hours later, unless I happened to think of them immediately after waking up.

Only, this doesn't seem to be entirely true. I've not infrequently had the experience with dreams, when I can "remember" details of being in places and situations and in the company of people that I've encountered in other dreams, perhaps not at all recently. So it seems that there is some sort of long term memory mechanism and storage capability that is specifically dedicated for use while dreaming. Perhaps this is just an aspect of the déjà vu effect.

Another intesting question about the state of consciousness during sleep is whether, or to what extent, the brain continues to engage in creative problem solving. We all know about the advice, when one has a difficult problem, to "sleep on it". This does seem to help a little, but probably it's more a case of letting sleep restore the freshness and alertness of one's mind. Ceasing to think about problems for awhile (whether hours or days) often has similar benefits. I'd say that I experience creative insights into problems rather more often in some place like the shower or out on a walk than I do right after awakening. So it doesn't seem to me that a great deal of actual ratiocination is going on during sleep. At least in my experience.

One last sort of observation, concerning how attention facilitates memory. I think most people find it a little difficult to recall what they've had to eat for lunch even a day or two ago, certainly a month or even a week ago. Unless, that is, there was something unusual about the circumstances of the meal. Such as eating something one hasn't tried before, or at least not for a long time. Or having a meal in a restaurant or location one hasn't eaten in often (or ever). In such cases, one tends to recall many little details of the experience, not just the items in the meal itself. For instance, one tends to remember noticing specific ingredients in what's eaten, and what flavors seemed to be especially pleasant or unpleasant.

When I think about it, I can still recall where I was the first time I had a cola beverage, and how I enjoyed it. I was only six or so. Now, perhaps what I can remember was not actually the first time. And perhaps I'm only remembering past experiences of having that memory. But still... this is about an experience that was decades ago, and without particularly intense related emotions, just general pleasure. But the experience was marked by having my full attention at the time. Needless to say, I can't summon up the perceptual experience of (probably) any other consumption of a similar beverage... except the one I had today.

From that experience, I draw the conclusion that attention is a mechanism which is separate from consciousness, yet which regulates it in such a way that essentially permanent long term memories can be formed. I don't think it's too much of a stretch to imagine that specific biological features will eventually be identified that implement the mechanisms of attention and consciousness in general.

Induced Pluripotent Stem Cells II

In this article from the April 4 Science, which I mentioned here, several research reports dealing with induced pluripotent stem cells were discussed. One of these I covered in the post I just noted.

Another just as important report apparently has not yet been formally published, but is (at least temporarily) available online since February 14 at Science Express:

Generation of Pluripotent Stem Cells from Adult Mouse Liver and Stomach Cells

                                                         Induced pluripotent stem (iPS) cells have been generated from mouse and human fibroblasts by the retroviral transduction of four transcription factors. However, the cell origins and molecular mechanisms of iPS cell induction remain elusive. This report describes the generation of iPS cells from adult mouse hepatocytes and gastric epithelial cells. These iPS cell clones appear to be equivalent to ES cells in gene expression and are competent to generate germ-line chimeras.

It's not surprising that this is significant research, as it's from the same team of Shinya Yamanaka that was the first to report successful creation of induced pluripotent stem cells. (See here.)

So what is this research about? Well, the investigators used the same four transcription factors (Oct3/4, Sox2, Klf4, and c-Myc) as employed in the majority of previous iPS studies. However, instead of applying the transcription factors to fibroblast cells, they were applied to two types of epithelial cells instead.

Fibroblasts are part of a body's connective tissue. They are involved in structure and support for other tissues and contain large amounts of the protein collagen. They do not divide for the most part, and so it is especially significant that it was possible to reprogram them into a stemcell-like state at all.

Epithelial cells, on the other hand, line the inner and outer surfaces of various body structures, including skin and the gastrointestinal tract. Such cells divide more frequently. They have to, in order to replace other cells of the same kind that are exposed to hostile environments. Epithelial cells also tend to be more adherent to other cells, because they more highly express an adherence protein called E-cadherin.

In some sense, then, epithelial cells are a little more like stem cells to begin with, so one might expect better results when attempting to reprogram them.

This expectation seems to have been met. One of the key differences the researchers found is that reprogrammed epithelial cells had less tendency to form cancerous tumors in mice into which they were included. Certainly not an inconsiderable advantage. This characteristic may be related to the finding that c-Myc seems to play a less essential role in reprogramming epithelial cells.

Specifically, reprogramming of epithelial cells was almost as efficient when c-Myc was not used as when it was included with the other three transcription factors. Yet it was not possible to accomplish reprogramming if any of the other three factors was omitted. In contrast, the efficiency of reprogramming fibroblasts dropped by 90% when c-Myc was omitted.

Another intriguing difference was that reprogrammed epithelial cells contained higher levels of expression of β-catenin than reprogrammed fibroblasts did. (You may recall – see here – that β-catenin is an important part of the Wnt signaling pathway.) In this regard, the reprogrammed epithelial cells are more like true embryonic stem cells than reprogrammed fibroblasts are. It's probably not a coincidence that expression of Nanog is stimulated by β-catenin, (see here), since Nanog is considered important for maintaining stem cell pluripotency.

A further advantage of the use of epithelial cells is that many fewer retroviral "integration sites" were needed to include the transcription factor genes into the cell genome, in comparison with fibroblasts. This is another way the risk of cancer is reduced.

TOR signaling and cancer

Another recent development pertinent to the discussion of TOR signaling and cancer (see here), is the announcement of preclinical findings about a potential anti-cancer drug that may act against ovarian cancer. The drug works by inhibiting the mTOR signaling pathway. (mTOR is the mammalian form of TOR.)

This is not at all the first anti-cancer drug that's come along with a similar mechanism of action. But it's still interesting, because any drug that affects TOR signaling has the potential of also causing unwanted side effects, since TOR signaling is involved in so many cell processes. Presumably some effort has been made to find reasons why the effect of the drug should be limited to cancer cells.

The drug is called NV-128, and has been developed by an Australian biotech company called Novogen. Since the drug hasn't yet entered clinical trials in humans, it could take a decade or so (as usual) to perform enough testing to determine that NV-128 is actually effective, and relatively safe.

Anyhow, here's the news release:
Drug Compound Leads To Death Of Ovarian Cancer Cells Resistant To Chemotherapy

                                                                       In a discovery that may be useful for maintaining remission in chemo-resistant ovarian cancer, Yale scientists report that pre-clinical studies have shown the drug compound NV-128 can induce the death of ovarian cancer cells by halting the activation of a protein pathway called mTOR.

Many traditional cancer drugs work by triggering cell death via apoptosis. Unfortunately, apoptosis needs enzymes called caspases to work, as explained here. And cancer cells may develop a circumvention of this mechanism by turning down the production of caspases, which are needed to allow mitochondria to respond to apoptosis signals. NV-128, however, is able to overcome this problem by triggering caspase-independent cell death.

In cancer cells, mTOR signals enhance tumor growth and may be associated with resistance to conventional therapies. Inhibition of mTOR could shut down many of these survival pathways, including proteins that protect the mitochondria of cancer cells.

Here's the Novogen press release:

Novogen’s NV-128 shown to target the akt-mTOR receptor in chemoresistant cancer cells

                                                                            NV-128 is unique in that it does not induce caspase-mediated apoptosis which can be non-functional in chemoresistant cancer cells due to accumulated mutations in tumour suppressor/promoter genes and over-expression of anti-apoptotic proteins. Rather, NV-128 uncouples the akt-mTOR­P70S6K signal transduction cascade which has a key role in driving protein translation and uncontrolled cancer cell proliferation. Further, NV-128 induces mitochondrial depolarization via a novel pathway involving the autophagy protein Beclin-1 and Bcl-2, thereby resulting in endonuclease G translocation to the nucleus and cell death.

The same research group that presented the findings just mentioned has also done work on ovarian cancer itself, and been able to locate cancer stem cells for this type of cancer:

Ovarian Cancer Stem Cells Identified, Characterized

                                                    Researchers at Yale School of Medicine have identified, characterized and cloned ovarian cancer stem cells and have shown that these stem cells may be the source of ovarian cancer's recurrence and its resistance to chemotherapy.

As already mentioned, NV-128 is not the only drug under investigation for attacking cancer by targeting the TOR pathway. In fact, almost a year ago, the first anti-cancer mTOR-inhibitor received FDA approval. It's Toricel (temsirolimus), an intravenous drug from Wyeth Pharmaceuticals, for kidney cancer. Novartis has an oral drug (everolimus) for kidney cancer in Phase III trials. (It's already been approved by the FDA as an immunosuppressant to prevent rejection of organ transplants.) Interestingly, and unsurprisingly, everolimus is a derivative of Rapamycin (sirolimus) – an anti-fungal and immunosuppressive compound – which led to the original discovery of mTOR. Everolimus works similarly to Rapamycin as an mTOR inhibitor.

The American biotech company Ariad Pharmaceuticals has a small molecule anti-cancer mTOR inhibitor called deforolimus in intermediate clinical trials for a variety of solid cancers, such as sarcomas, endometrial, prostate, breast and non-small cell lung cancers. The company describes the drug as "a novel small-molecule inhibitor of the protein mTOR, a “master switch” in cancer cells. Blocking mTOR creates a starvation-like effect in cancer cells by interfering with cell growth, division, metabolism, and angiogenesis." Last summer Ariad entered into a major partnership with Merck to develop and test the drug, so this is an indication that the drug has definite promise.

Ariad has a nice video you can download, which explains a bit about how their drug works, and about TOR signaling in general. I highly recommend having a look at it, since it covers upstream signals that activate mTOR (growth factors, amino acids, oxygen, energy), downstream effects (synthesis of proteins for cell growth, cell division, metabolism, and angiogenesis). It notes that certain other signaling proteins (PTEN, Akt, PI3K) cause overactivation of mTOR, and it points out that mTOR stimulates the production of the cyclin D cell division protein.

 

Black holes exist

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

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

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

Even very recently one still sees theoretical studies that offer alternatives to the standard relativisic model of black holes.

Nevertheless, to the consternation of skeptics, the evidence for the correctness of the standard model of black holes just continues to pile up:
Quasar tests general relativity to the limit

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

And actually, the more significant part of that research is its validation of general relativity in very strong gravitational fields:

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

The amino acid chirality mystery

If the analysis here is correct, it solves one of the more puzzling mysteries of life on Earth – namely, the fact that all 20 amino acids found in biological proteins are "left-handed".
Meteorites Delivered The 'Seeds' Of Earth's Left-hand Life, Experts Argue

                                                                   In a report at the 235th national meeting of the American Chemical Society, Ronald Breslow, Ph.D., University Professor, Columbia University, and former ACS President, described how our amino acid signature came from outer space.

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

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

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

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

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

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

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

But there's another way out, because we know that in fact amino acids can form in interstellar space, since they were found in parts of the Murchison meteorite (and later others) that were uncontaminated with Earthly material. Furthermore, there's one definite way that amino acids which existed originally in an equal mixture of L and R forms on a chunk of rock hurtling through space could have their proportion tilted in one direction or the other:

These amino acids "seeds" formed in interstellar space, possibly on asteroids as they careened through space. At the outset, they have equal amounts of left and right-handed amino acids. But as these rocks soar past neutron stars, their light rays trigger the selective destruction of one form of amino acid. The stars emit circularly polarized light--in one direction, its rays are polarized to the right. 180 degrees in the other direction, the star emits left-polarized light.

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

So, one asks, is it possible that this imbalance of R and L amino acids was transferred from a meteorite to prebiotic Earth? In a series of experiments Breslow confirmed that this could happen:

Breslow simulated what occurred after the dust settled following a meteor bombardment, when the amino acids on the meteor mixed with the primordial soup. Under "credible prebiotic conditions"-- desert-like temperatures and a little bit of water -- he exposed amino acid chemical precursors to those amino acids found on meteorites.

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

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

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