A new kind of mind control

Remember subliminal messages? Those images supposedly flashing too quick for your mind to register, but still managing to convince you to drink more soft drinks, eat more fries, buy a luxury car? While those days may not be over yet, new forms of mind control (albeit more biological than psychological) are emerging thanks to the tiniest of creatures, the bacteria.

A friend of mine, Cal, recently alerted me to an interesting article about optogenetics. If you’re not familiar with the word, that’s because it’s very new, and it essentially means playing with light and genetics at the same time. It’s all the rage in neuroscience right now and articles such as the one I’ll be describing in this post are popping up every week.

It all starts with a tiny little pump called halorhodopsin found in bacteria. This pump sits at the surface of cells and pumps chloride ions from outside the cell to the inside (table salt is sodium chloride - same chloride). Cells use chloride for different reasons, but this pump can be especially relevant for brain cells (called neurons). Neurons pass information to one another through electric currents. And it just so happens that chloride ions are charged negatively. That means that if many chloride ions accumulate inside a neuron, the cell becomes increasingly charged negatively, making it harder to reach the positive threshold it needs to pass currents to other neurons.

Other types of chloride pumps already exist in your brain cells, but almost nobody makes a fuss about those. So how is halorhodopsin different? This is where the “opto” from “optogenetics” comes in. This particular pump is activated by light. This means that if neurons have this special pump, you can control whether they are active or not just by flashing a light onto them.

In a recent paper published in PNAS, the researchers genetically engineered zebrafish so that their brain cells expressed the special light-activated chloride pump. The researchers then recorded the electrical signals generated by the brain cells (they look like spikes, much like what you would see on an EEG). I don’t know if you can imagine what kind of feat that represents, but I’d like to make a motion to modernize the saying “like finding a needle in a haystack” to “like poking an electrode into a brain cell of a live fish”. Once they knew what the signals looked like in normal conditions, they shone the light on the fish*, and amazingly, all the brain cells went quiet. It worked! The light activated the pump, negatively charged chloride ions accumulated in the cells and made it too difficult to reach the spiking threshold.

The black lines are the current spikes that normally occur when brain cells transmit information. The yellow section is when the researchers shone the light: no more spikes.

Now a fish doesn’t have that many brain cells to start with, and since it spends most of its life moving it’s pretty safe to assume that a large portion of the fish’s brainpower is devoted to swimming. The researchers thought they had a pretty cool tool to test this, and so they did. They put a bunch of genetically-engineered zebrafish in a dish, watched them swim around for a bit, and then shone a light on them*. Sure enough, the fish stopped moving and lost coordination. I realize we’re talking about lousy, bottom-of-the-food-chain fish here, but think about it: *that’s* mind control.

The article continues to great lengths, going into details about what specific part of the brain controls the swimming behavior and describing control experiments that confirm that this isn’t a fluke (i.e. the fish aren’t just spooked by the light). All things considered, it’s a very elegant example of how to use optogenetics to better understand the brain. And the relevance of these advances lies in the increased understanding of not only the brain but also diseases of the brain. Recently, these new techniques used in animal research gave us important insights into Parkinson’s disease.

What about using these tools as ways not only to understand disease, but also to treat them? What if we made our own brain cells express this special pump so we could use light to activate or inhibit different areas of our brains? While this may seem like science fiction right now, don’t be so sure. I attended a talk on optogenetics recently, and the researcher firmly believed that this emerging field of neuroscience would eventually cure blindness. In the meantime, let’s see if you can think of all the ethical questions this would raise…

* For these experiments, the researchers used fish in the larvae stage. The skin of the fish at that point is transparent, and this allows the light to reach the brain cells.

This little zebrafish is doing his best to contribute to science.

Reference: Optical control of zebrafish behavior with halorhodopsin. (2009) Arrenberg, A.B., Del Bene, F., Baier, H. Proc Natl Acad Sci USA, 106(42):17968-73.

Yet another reason for a good night's sleep

How much do you sleep at night?

If you’re like most of the people I know, the answer is “not enough”. There’s a reason Starbucks coffee shops are popping up literally meters away from one another. Everybody has a reason to be sleep-deprived: new kid, big job, World of Warcraft, etc. So what if we’re cutting the night short a few hours? Other than the need for an overpriced coffee (or two, or three), it should be just fine, right?

Maybe not, if you believe the latest research on sleep and Alzheimer’s disease.

Alzheimer’s disease, a debilitating form of memory loss and cognitive decline, is the most common form of dementia. It is thought to be caused at least in part by amyloid beta (A-beta), a peptide (short protein). Your brain cells (neurons) normally make some A-beta. The problem that arises with Alzheimer’s disease is that neurons make too much A-beta, and these molecules aggregate together in chunks. It’s those A-beta chunks that are toxic, and their formation is concentration-dependent, which means the more A-beta you have floating around, the higher the probability of toxic chunks forming.

The recent article published in the journal Science looks at levels of A-beta in the brains of normal mice and in the brains of a mouse model of Alzheimer’s disease. The researchers studied the mice when they were 3 months of age, so well before big deposits and chunks of A-beta start occurring.

The interesting finding of this study is that the levels of A-beta in the brains of both types of mice were significantly correlated with the amount of time they spent awake. More time spent awake lead to more A-beta. Because the control, normal mice also exhibited this relationship, it means that it is not linked to the disease. It’s just a normal fluctuation of A-beta levels linked to the sleep-wake cycle. To be certain this link was relevant for human physiology, they also tested this in healthy humans and, sure enough, they observed the same correlation.

Not surprisingly, when the researchers proceeded to sleep-deprive the mice, they showed an even larger increase in A-beta levels. This increase was also observed when the mice were given a drug that promotes wakefulness (don’t extrapolate this to coffee just yet… But maybe keep it in mind…). The study also points out that the Alzheimer mice who are sleep-deprived showed much greater numbers of A-beta chunks (the toxic stuff) compared with non sleep-deprived mice.

If you come to Scientific Chick for relevant findings, this one is for you. The study essentially implies that optimizing sleep time could potentially inhibit the formation of chunks of toxic A-beta and slow the progression of Alzheimer’s disease.

We all know that Alzheimer’s disease is terrible, and that sleeping in is glorious. Let’s just put two and two together, shall we? Easier said than done, I know…

Mr. Minou gave up on caloric restriction but approves of this new approach to ward off age-related diseases.

Reference : Amyloid-{beta} dynamics are regulated by orexin and the sleep-wake cycle. (2009) Kang JE, Lim MM, Bateman RJ, Lee JJ, Smyth LP, Cirrito JR, Fujiki N, Nishino S, Holtzman DM. Science Sep 24. [Epub ahead of print]

Yet another reason to exercise

Last weekend I went for a bike ride and when I reached the bottom of the big hill leading to UBC, I noticed quite a bit of activity going on. I didn't pay too much attention at first, but once I was booting up the hill, I was passed by several senior citizens on top-notch bicycles and I started getting curious. I asked a person who seemed to volunteer for the event what was going on. As it turns out, I was cycling right in the middle of the BC Seniors Games. Now for those of you who might not know me, my thesis research has to do with aging and the brain and nothing warms my heart like witnessing older adults and seniors exercising. I had just hit the jackpot!

The reason I'm so enthralled to see seniors exercise is because it is the single best thing they can do to preserve their brains. Today's paper highlights recent research done in California that shows just that.

First, a bit of background. You have a gene called APOE (mice also have it). It comes in 3 flavors, and each person only has one of the three: APOE2 (not important for today’s article), APOE3 and APOE4. If you got lucky and scored the APOE3 kind, all is well. If you happen to be in the 20-25% of the population who has the APOE4 kind, you may be in trouble: APOE4 is a known risk factor for Alzheimer's disease. Does it mean you'll for sure get Alzheimer’s disease? No, but you are 10 to 30 times more at risk of developing Alzheimer's disease if you carry the APOE4 gene.

In this paper, researchers compared old APOE3 (normal) and APOE4 (at risk for dementia) mice. In general, aged APOE4 mice experience cognitive decline faster and earlier than APOE3 mice. The researchers were interested in studying whether exercise (running on a mouse wheel!) had any effect on this cognitive decline.

The researchers used cognitive tasks that rely on a part of the brain that's important for memory, the hippocampus. One of the tasks, called place recognition, involves putting a mouse in an arena with two objects. The mouse is then removed from the arena, one object is moved, and the mouse is put back in the arena. Presumably, a normal mouse will then spend more time exploring the object in the new location. For this task, the aged APOE4 mice were initially impaired compared with the APOE3 mice. This means that during the second trial of the task, they tended to explore both objects for similar amounts of time, instead of spending more time on the object at the new location. This result suggests that the APOE4 were unable to remember the initial object locations well. The good news? Mice who exercised did significantly better at this task. Interestingly, this was valid for both APOE3 and APOE4 mice. Even more interestingly, exercise improved the scores of both types of mice for all the tasks that tested the hippocampus.

What's going on in the brains of these exercising mice? It is thought that exercise increases the levels of a protein called BDNF (for Brain-Derived Neurotrophic Factor). BDNF regulates many important functions in the brain, including the making of new neurons and the making of new connections between neurons, and these effects are thought to be important for memory.

Regular readers of Scientific Chick know not to get too excited when I report about animal studies. Well, I'm happy to add that the results that were observed in those mice were also observed in humans. In fact, there are countless human studies out there that confirm that physical activity is a powerful way to improve and maintain your cognitive abilities.

When I try to urge certain people to exercise (you know who you are), I almost always hear the same excuse: “Well, my uncle so-and-so never got off his couch and he lived to be 100!” In some cases, heredity can be on your side, that's true. But genetics can be quite the lottery, and it's important to keep in mind that several forms of cognitive decline, including the most common form of Alzheimer's (called “sporadic” in scientific lingo) are not hereditary.

So to all my older readers out there, I'll see you on the road at next year's BC Seniors Games. And if you're not ready for cycling, there's always the cribbage category.

Winners from this year's BC Seniors Games, cycling event. This could be you!

Reference: Exercise improves cognition and hippocampal plasticity in APOE epsilon4 mice. (2009) Nichol K, Deeny SP, Seif J, Camaclang K, Cotman CW. Alzheimers Dement. 5(4):287-94.

Children see, children do, but monkeys know better

I usually like to blog about recent articles, and I try to limit myself to papers published in the last 2-3 years. I’m going to make an exception this time and write about a publication from way back (2005). By scientific standards, 5 years ago is literally ancient (kind of like computer standards), but bear with me, this is going to be worth it (unlike a 5-year old computer).

Researchers from the UK were interested in finding out more about learning patterns, and about how our learning patterns differ from one of our close cousins, the chimpanzee. To test this, they subjected human children 2-4 years old and chimpanzees 2-6 years old to a simple task: retrieving a treat from a box.

In the first set of experiments, the researchers gave the chimps an opaque black box, and showed them how to open it to retrieve a treat inside. This wasn’t a simple pull-the-top-off kind of box, though. The box seemingly could only be opened following a series of specific steps: pulling a bolt, putting a stick in a hole, opening a door, etc. Chimps are quick-learners, though, and by imitating the researcher, they were soon able to retrieve the treat, no problem.

How well did the human children to at the same task? Quite well. They too were able to learn how to retrieve the treat from the black box by copying all the steps the researcher showed them. It would have been slightly worrying otherwise. I mean, we’ve taken over the world, right? Surely we can teach our young how to open a silly box, right?

The second set of experiments was almost exactly the same as the first one, except this time the box was made out of clear plastic instead of being opaque. The researchers went through the same process of teaching the chimps how to open the box. But there’s a catch: with a transparent box, it became very obvious that most of the steps supposedly needed to open the box were irrelevant. All you had to do was open the door. Chimpanzees, our closest living relative, are quite smart, and dropped all the unnecessary steps. They didn’t bother with the bolt and the stick and all those irrelevant actions: they went straight for the door and grabbed the treat.

When it was time for the children to be tested on the clear box, they too got shown how to open it by the researchers, including all the unnecessary steps. And when it was their turn to do it, they obviously…

Started pulling the bolt, putting the stick in the hole, etc.

Wait, what?

Did I get that wrong? I must have messed up the subjects… Wait… Nope. Those monkeys just fed us a piece of humble pie.

The researchers suggest that in the case of this study, the difference between how the chimps and how the children perform the task may have to do with a different focus of attention. Children pay more attention to the process of opening the box and the actions of the researcher, while chimps have their eyes on the prize, and focus more on the goal rather than the process. The researchers conclude by saying that imitation may be a human strategy that is often employed at the expense of efficiency.

The interesting thing about this article is that some news reports and descriptions of this experiment in magazines ended with a conclusion that more or less stipulated that our children imitated even the irrelevant steps of the task because that was the smarter thing to do, twisting the story around to make it sound like humans were superior to the chimpanzees in some way. Start your debate engines, but my opinion is that we should stop considering ourselves so superior. The results of this study are pretty straightforward. Do we really have to come up with a twisted interpretation of the results to make us sound like the winners? I would love it if we could just look at this experiment and say, hey, what do you know, we can learn something from the chimps.

Eyes on the prize, people. Eyes on the prize.

This monkey is laughing at you.

Reference: Causal knowledge and imitation/emulation switching in chimpanzees (Pan troglodytes) and children (Homo sapiens). (2005) Horner V., Whiten A. Anim Cogn 8(3):164-81.

Conquering cancer one virus at a time

Back in June, I participated in The Ride to Conquer Cancer, a 2-day bike ride between Vancouver and Seattle to raise money for BC Cancer. It was an extremely moving, positive and rewarding experience. It also gave me a chance to eat a piece of humble pie when 70 year-old cancer survivors (identified by flags on their bikes, adding to their wind resistance) would pass me going up the hill. The good news is that at the end of the 272 km, I was still smiling:

The bad news is that I didn’t conquer cancer.

Cancer research is well-funded, popular, and has been around for quite some time. So why can’t we get rid of this disease? The problem with cancer is that it’s tremendously difficult to target. Unlike cells infected by viruses and bacteria, cancer cells don’t display any obvious flags that something is wrong with them, which makes them challenging to distinguish from healthy cells. Therefore, most treatments for cancer involve killing a number of healthy cells, and that’s just not ideal.

Progress is being made, though, as a recent publication in the journal PNAS suggests. In this paper, a collaboration between researchers in California and in Japan lead to the discovery of a new way of identifying tumors for easier removal. They rely on an unlikely ally: viruses.

The researchers genetically engineered a special type of virus to carry a gene that codes for a fluorescent protein, GFP (for Green Fluorescent Protein - as simple as that!). If all the cells in your body were to be infected by that virus, you would glow (kind of like the famous puppy). While this would immediately up your popularity ranking at any science party, it doesn’t do much for treating cancer. So the researchers took it one step further and engineered the virus so that it would only express the fluorescent protein (make the cell glow) if the cell has an active telomerase. Telomerase in an enzyme involved in the replication of cells. If the telomerase enzyme is active when it shouldn’t be, it can cause cells to divide indefinitely, creating tumors. In fact, it is thought that over 90% of human tumors show telomerase activation. To sum it up, cells are infected with a virus that has a gene for a fluorescent protein, but only cancerous cells have an active telomerase, the switch that turns on the fluorescence. The result? Glowing tumors.

The benefits of these findings are two-fold. First, glowing tumors mean that surgeons can precisely remove the tumors without having to also remove a chunk of healthy tissue “just to make sure”. Second, tumors have a nasty habit of hitching a ride in your lymphatic system or your blood and disseminate throughout your body, making it very difficult to take out every little bit of sprouting tumor. With this innovation, all those little disseminated tumors can be identified and removed. Those two benefits together could greatly reduce the chance of a relapse, an important consideration when treating cancer. The researchers tested their mutant virus in two different types of animal models of cancer (colon and lung) with great success. While I’m usually worried at the prospect of glowing body parts, this research could have a big impact on cancer treatment.

If I want to give myself a chance to conquer cancer in 2010, I should probably spend less time on the computer and more time on the bike...

Glowing tumors

Reference: In vivo internal tumor illumination by telomerase-dependent adenoviral GFP for precise surgical navigation. (2009) Kishimotoa, H., Zhaoa, M., Hayashia, K., Uratad, Y., Tanakac, N., Fujiwarac, T., Penmanf, S., and Hoffmana, R.M. Proc Natl Acad Sci 106(34):14514-7.

Dating advice courtesy of your friendly neighborhood monkey

Dating advice websites abound with many different kinds of advice: good advice (don’t pick your nose), strange advice (date according to your blood type), not so good advice (Leos dating Leos need to hire domestic helpers). One suggestion that seems to pop up quite frequently is to mimic the body language of your date. He picks up his drink for a sip, you pick up yours. He strokes his hair, you stroke yours. He picks his nose, you pick your nose. You get the idea. As it turns out, in a social interaction context, we humans tend to unintentionally imitate what others are doing. Think of this as a team-building exercise: it’s a behavior that helps establish rapport, empathy and other fuzzy feelings toward each other.

A recent publication in the journal Science shows that behavior matching leading to increased rapport is not exclusive to humans, and it can also occur between different species.

The study looks at capuchin monkeys, a very social primate species. During the experiments, the monkey is given a ball to play with. On either side of the monkey’s cage stands an experimenter. One experimenter is mimicking what the monkey is doing with the ball (poking it, pounding it against the wall, trying to eat it… Mmmmm…), while the other experimenter is also playing with the ball, but not mimicking the monkey. The researchers show that not only do the monkeys look at the imitators more, they also spend more time hanging out close to the imitators and prefer to interact with the imitators in a food exchange game. The authors also did an important series of control experiments to show that these effects were not due to the monkeys perceiving more attention from the imitators.

So why are we subconsciously hard-wired to constantly be playing Simon Says? It is thought that the positive feelings resulting from behavior matching played an important role in human evolution by leading to higher levels of tolerance and by preventing aggressive behavior (to put it simply, by preventing us from beating each other up). The same principle probably applies to primates, and the empathic connection that results from imitation may explain the altruistic tendencies observed in the behavior of capuchin monkeys.

Next time you catch yourself winking back at someone who winked at you, or laughing at a joke you didn’t get because everyone else is laughing, keep in mind it’s for the greater good. After all, even monkeys know that imitation is the sincerest form of flattery.

Scientific Chick readers applying their new found knowledge
(Image from Loldogs)

Reference: Capuchin monkeys display affiliation toward humans who imitate them. (2009) Paukner, A., Suomi, S.J., Visalberghi, E., Ferrari, P.F. Science 325:880-882.

Need some real estate advice? Ask an ant.

What does it mean to be rational?

In a biological context, rationality means that when animals (including humans) are making a decision, they choose the option that maximizes their fitness benefit. For example: my cat, Mr. Minou, prefers to eat canned food rather than grass. Canned food provides him with more nutrients, more protein, and more energy than grass: it has a fitness benefit for Mr. Minou. Even if he is presented with a third option, say, dry cat kibbles, Mr. Minou stills prefers canned food, because it still has the highest fitness benefit (and, obviously, kibbles taste gross).

Pretty straightforward so far. So, being the advanced species we are, humans must be rational beings, right?

Wrong.

Here is another example. Let’s say you’re shopping for a new house. You have two equally important criteria for your new house: it must have big windows to get lots of natural light in, and it must have a big garage to store all your stuff. There are two houses on the market. House A has big windows but a small garage. House B has a big garage but small windows. Rationally, humans in this position have a 50% chance of picking either house.

Suddenly, a third house is made available on the market. House C has big windows, but NO garage. In a situation like this, humans overwhelmingly put rationality aside and shift their pick to house A with the large windows but the small garage, because the perceived value of house A increased when comparing it with other available houses. However, houses A and B have unchanged value!

The reason for this shift is that as decision-makers, we don’t assign absolute values to options, we assign relative values. We like to compare. And comparing can be misleading.

Recently, two American researchers wondered about the rationality of collective animals, such as ants. The researchers figured that just as choices we make result from the complex interactions of many brain cells, the decisions that an ant colony makes might similarly stem from a complex network of interacting insect. Ant societies act as unitary decision-makers, jointly deciding on things like a single travel direction, or a nest site. The researchers decided to take advantage of the ants’ nest-seeking strategies to test their rationality.

The ants in the study live in natural holes like hollow branches, and are able to emigrate to a new nest if their current nest is damaged. Colonies seeking a new nest reach consensus on the better site among the new options based on entrance size, cavity dimensions, interior light level, etc. The way a colony reaches consensus is fascinating: a few scout ants head out to assess the quality of potential homes. When a scout finds a potential new home, it leaves to recruit more scouts, who will then recruit more scouts, and so on. The strength of this technique lies in the key fact that the higher the quality of the nest an ant finds, the faster it will recruit other ants. Eventually, a threshold of recruiting is reached, and non-scout ants are recruited and eventually the entire ant colony is moved.

The researchers first established that ant colonies prefer nests that have small openings and low inside light levels. They then assessed the susceptibility of ant colonies to irrationality by comparing the colonies’ preference for new nests with different attributes in a very similar way to my house example: nest A has a dim interior but a large entrance size, and nest B had a brighter interior but a small entrance size. In this case, the ant colonies showed no preference for either site, which is very rational of them.

The researchers then added one of two decoy nests. Decoy nest A2 was just as dim as nest A, but had an even larger entrance diameter. Decoy nest B2 had the same entrance diameter as B but was even brighter than B. In summary, each decoy nest had a good feature equivalent to that of A or B, and the other feature was worse.

Well, the study suggests that we should turn to ants for real estate advice: the presence of either decoy did not affect the proportion of colonies choosing A or B. This means that even with the decoy, the ant colonies recognized that A and B had equal fitness values, and that the option of the decoy did not change the fitness values of the original nest sites.

So what is the ants’ secret for being so rational? The most plausible explanation is that for the most part, each scout ant only visits one site. If it’s good, it recruits, and if it’s crummy, it moves on. No comparing with the one next door. In this case, the fact that individuals in the decision-making strategy lack either the opportunity or the ability to compare all the options offers some protection against irrational, fitness-reducing errors.

Is this relevant for us, other than the piece of humble pie we must eat when realizing that ants can be more rational than we are? Well, when faced with a decision, it can be helpful to remember to evaluate each option for its absolute value, and not its relative value.

Mr. Minou himself occasionally forgoes rationality and chooses to eat grass. I suspect he only does it for the pleasure of watching me wash puke from the floor afterwards. Maybe in some twisted way, making sure I clean up after him confers him some kind of fitness benefit…

Mr. Minou being irrational

Reference: Rationality in collective decision-making by ant colonies. Edwards SC, Pratt SC. Proc Biol Sci (2009) Jul 22 [Epub ahead of print]