Sunday, July 19, 2015

Pandas are lazy!

Pandas are closely related to carnivorous mammals (like all the other bears), but they consume mostly bamboo.  Their digestive tracts are short and adapted for digesting meat, not cellulose that is found in plants.  In fact, they only digest about 20% of all the bamboo they eat, and they eat a lot of bamboo (30-60 pounds a day)!  How are these large, adorable bears able to get enough energy to function from their inefficient digestion of bamboo?  Researchers in China and Scotland addressed this question by studying captive and wild pandas, described in a recent Science article.

Low energy expenditure
Nie et al. measured the daily energy expenditure of the pandas and found that they used an unusually low amount of energy, only 37.7% of the predicted value based on their body mass.  In fact, pandas are expending energy at levels similar to the three-toed sloth, the epitome of a low-energy mammal.  The measly amount of nutrients they get from all that bamboo would be able to sustain such a low energy expenditure, so that’s how the panda is able to get by with such a maladapted digestive system.

How do the pandas manage to spend so little energy?  There must be some adaptations that are allowing the panda to survive without expending so much energy.  The authors found a number of these adaptations:

1) Pandas have a thick layer of fur, so they can maintain their internal body temperature with less heat loss through the skin.  The researchers measured temperature at the surface of various animals and the pandas consistently were cooler than other mammals (like a cow or dog).  Their internal body temperature would be considerably warmer because the fur helps insulate them, so they don’t have to spend as much energy on maintaining their body temperature.

2) Pandas are lazy.  No surprise: pandas spend more time inactive and when they do move, it is slowly.  So that is less energy needed for muscle contractions.

3) Pandas have small brains, livers and kidneys, so their organs need less energy.

4) Pandas have a low resting metabolic rate, which is driven by the thyroid hormones, T3 and T4.  In fact, levels of these two hormones were considerably lower than for other mammals of the same body mass, even lower than a hibernating bear.  The thyroid hormones regulate protein, carbohydrate and fat metabolism, as well as growth and development.  If the pandas don’t need to produce as much heat or energy, then there is no reason to have a high metabolic rate.

Interestingly, pandas have a single mutation in a gene called DUOX2, which is not found in any other mammals.  DUOX2 encodes for a protein that is necessary for the production of T3 and T4.  The mutation causes a premature “stop” in the protein, so it likely affects the function of DUOX2. 

In other words, pandas cannot synthesize T3 and T4 as well because of this mutation, so they have a reduced metabolic rate.  But that’s okay, because they are good at maintaining their body temperature and they have developed an enjoyable lifestyle of relaxing and eating.  The fact that their digestive tracts have not evolved for plant digestion is alright given the fact that they don’t really need that much energy from their food.  So it all works out: pandas are able to survive on their diet of bamboo and we can watch them sit around.

Sunday, March 22, 2015

Bigger brains with Frizzled HARE

We have all heard that the sequence of human DNA differs from chimpanzee DNA by only about 1%.  Yet humans are capable of building complex civilizations while the chimps are still eating bugs in the forest.  If you compare the human brain to the brain of any other primate, it’s easy to see where our sophisticated cognitive abilities come from. 


DNA is the blueprint for making proteins, cells and organs, so is there something special hidden in that 1% sequence difference that gives humans bigger brains?  In particular, scientists have focused on regions in the human genome that have undergone rapid sequence changes in the human lineage, but not in other primates.  Besides looking for differences in genes that make proteins, we can also look for changes in regulatory regions, like enhancers, that control when and where the genes are expressed.

A recent paper in Current Biology by Boyd et al. explores these questions by studying a human-accelerated regulatory enhancer (HARE5), which differs significantly between humans and chimps.

Enhancer activity of HARE5

How do you study enhancers?  One way is to use a reporter gene.  Enhancers drive expression of nearby genes, so what if you swapped out a nearby gene and replaced it with a gene for a fluorescent protein?  Then you can look at your organism and wherever you see the fluorescent protein, the enhancer is active, meaning that the normal “nearby gene” is normally expressed in those cells.  Instead of doing these experiments with chimps and humans, which would take forever and be unethical in some cases, the authors put these reporter constructs into mice.  The enhancers from the chimps and humans drove expression of the reporter gene in the embryonic mouse brains.  The gene adjacent to the human enhancer was expressed earlier in development and more strongly than when placed next to the chimp enhancer (in other words, a lot more protein is being made).

Reporter gene experiment.  The mouse brain images are actual results from Figure 2 in Boyd et al. (2015).

This tells us that whatever normal gene is near HARE5, it is probably expressed earlier and way more in humans than in chimps.  There are just 10 sequence differences in the human HARE5 (i.e. mutations), which is enough to affect the way the enhancer functions and activates expression of genes. 

Frizzled expression is regulated by HARE5

So which genes are near the HARE5 sequence?  The closest gene is called Frizzled 8 and it is a receptor that responds to signals sent by other cells.  Frizzled 8 (FZD8) is a well known component of the Wnt signaling pathway that regulates many aspects of embryonic development, including neurogenesis (formation of new neurons).  The authors demonstrate that the mouse HARE5 physically interacts with Fzd8, which is a necessary  first step of gene expression, so Fzd8 is likely affected by the HARE5 sequence differences in humans and chimps.

The authors wanted to see what would happen to development of the mouse brain when Fzd8 is expressed in the same pattern as in humans or chimps.  They repeated the earlier experiments, but this time instead of using a reporter gene, they put the mouse Fzd8 gene next to the chimp or human HARE5 sequence.  They injected these DNA constructs into mice and waited to see what would happen to embryonic brain development.  When the chimp-HARE5 was driving expression of Fzd8, not much changed in terms of mouse brain development.  However, when the human-HARE5 sequence was activating the mouse Fzd8 gene, the mouse brain grew 12% bigger!! 

Let me be clear here-- they are not expressing the human Fzd gene in mice.  No, they are using the human enhancer to drive expression of the mouse Fzd8 gene, so presumably it is expressed more and earlier in development (like they saw in the reporter gene experiment).  The neural progenitor cells (pre-neurons) divided faster than in a normal mouse, leading to formation of more neurons, and a bigger brain! 

10 sequence changes in an enhancer may be one reason why I am able to write and you are able to read and understand this blog.  Whoa.  No news yet about whether these mice with bigger brains are also able to read and write… I’m sure they’re saving that for another paper.

I should say too, that there are probably a number of other similar changes to other enhancers and genes that all led to the rapid development of the big ol’ human brain.

Here's another blogger's take on this paper 

Sunday, January 11, 2015

Smart phone use changes the brain

One of the most remarkable things about our brains is how organized they are. Sensory information from our eyes, mouth, skin, nose and ears goes to different locations in the brain. For example, visual signals are processed first in the very back of the brain, whereas sensations of touch and pain activate the middle region of the brain called the somatosensory cortex.

Functional organization of brain cortex. (Source:
Remarkably, the brain gets even more organized from there. Within the visual cortex, there are columns of neurons that only respond to light that is horizontal and others that only respond to lines that are tilted 45 degrees. The somatosensory cortex is also highly organized, with different parts of the body represented by specific sets of neurons. If you were to send electrical shocks into one specific area of the somatosensory cortex to activate those neurons, you may elicit feelings of touch from the right thumb, even though the subject is not being touched at all. Move those electrical signals over slightly to another area, and the subject may feel touch instead coming from the palm of their hand.

Wow, right? But here’s the real mind blower: this organization can change over time as the person experiences different sensory inputs. If you are a violin player, you feel the strings with your fingertips a lot, so the fingertip part of the somatosensory cortex is super active. This extra activity allows the fingertip representation in the brain to grow and recruit nearby neurons to also respond to touch in the fingertips. The cortical representations are “plastic” and always changing with use.

A violin player may practice this one particular skill a lot, but what about other activities we do everyday with less intensity, like using smart phones? Think about how often you are swiping the screen with your thumb. That’s a lot of sensory information being sent to the thumb part of your somatosensory cortex. Would this increase the thumb representation in your brain? A recent paper by Gindrat et al. addressed this exact question using EEG to record brain activity in smart phone users versus people with the old-style cell phones.

How can you actually measure the area of body representations in the somatosensory cortex? You could stick electrodes into people’s brains and record the activity in their neurons, but that’s a little invasive. You could put them into a MRI machine and measure brain activity when you touch their thumbs, but that is time consuming for so many subjects (37 total). Instead, the authors used a method known as electroencephalography, or EEG, which consists of 62 surface electrodes placed on the scalps of the subjects. Each electrode records the summed electrical activity from all the neurons positioned right under the electrode. Before an experiment, all the electrodes would be picking up a baseline of activity from lots of different neurons firing asynchronously. However, during an experiment, there is a single stimulus (like touching the subject’s thumb), which elicits activity in a lot of neurons all at the same time. This activity summates to give one large response called the event related potential (ERP), which is recorded by the nearest electrodes.

EEG electrodes record brain activity (source: Wikimedia commons)
Finger representations in smart phone users
The ERPs for the thumb, index finger and middle finger were larger for the smart phone users than for the non-touchscreen users. There was a correlation between the amount of phone use per hour and the ERP, so the more use, the greater the ERP, which is to say the more activity in the somatosensory cortex. The number of electrodes recording the ERP was greater in the touchscreen users, so when you touch the thumb of a touchscreen user, a larger part of the somatosensory cortex responds. In other words, the thumb representation was larger in smartphone users who use their thumbs more often.

The more recently the subjects had used their phones intensely, the larger the ERP for the thumb, which indicates that brain remodeling occurs on a very short time scale (within 10 days in this experiment). Interestingly, there was no correlation between ERPs and the age at which the subject started using a touchscreen. This is in contrast to the previous experiments done with trained violin players, which did show a correlation between the size of the finger representations and the age at which they first started playing. The authors suspect that a trained violinist develops a more stable sensory representation than touchscreen users who are casually using their phones (as opposed to years of disciplined practice).

So the take-home message is that normal day-to-day activities can influence brain plasticity and the way our sensory representations are organized in our brains. This could be a good thing, because subjects develop better touchscreen skills. On the other hand, the enlarged thumb representation could cause focal dystonia, which is characterized by involuntary muscle contractions and sometimes pain, as the various body part representations lose their distinct boundaries and start to overlap. This probably won’t be a problem for most phone users, but be forewarned all you smart phone addicts out there.

Monday, January 5, 2015

What big nuclei you have!

Eggs get ready for fertilization by producing and storing all the proteins necessary for early embryo development.  After fertilization, there are a series of rapid cell divisions without growth, producing a lot of small cells (here's a video).  At some point during this process, the embryo switches over from using the proteins from mom, to expressing their genome to make their own proteins.  This transition to embryonic transcription is known as the midblastula transition, or MBT.  How does the embryo know when it is time to turn on gene expression? 

One theory is that the ratio of nuclear to cytoplasmic volume (N/C volume) is the trigger for MBT.  The nucleus is where DNA is stored within a cell; this is where gene expression occurs.  The cytoplasm is the goo that the nucleus sits in.  During those rapid early cell divisions, nucleus size does not change much, while the cytoplasm in each cell keeps getting smaller and smaller.  The N/C volume increases, since the cytoplasmic volume is decreasing.  Is there a certain threshold of N/C volume, above which the embryo switches on gene expression?

Jevtic and Levy did a series of clever experiments, using frog embryos to address this question, which was published today in Current Biology.  In Xenopus laevis frogs, the midblastula transition always occurs after the 12th cell division.  The researchers manipulated the nucleus size in the frog embryos to see if that would change the timing of MBT.

Changing nuclear volume
The authors were able to increase nucleus volume by injecting embryos with mRNA for importin and a type of lamin.  Importin acts as a shuttle that brings other proteins into the nucleus, including structural proteins that make up the nuclear envelope.  Lamins form the inside of the nuclear envelope, so by injecting the mRNA for these two proteins, they caused overexpression of nuclear proteins that will make the nucleus grow larger.  To decrease nuclear size, they instead injected mRNA for a protein that causes another cell structure to grow (the ER) at the expense of the nucleus.

They injected the mRNAs and a red dye into one cell in the two-cell stage.  When this cell divides, its daughter cells inherit the red dye and the mRNAs and proteins that change the nucleus size.  Thus, by the time a normal embryo is ready to undergo MBT (the midblastula transition to express their own genes), half of it will be red and have abnormally sized nuclei and the other half will be normal and act as an internal control. 

N/C volume triggers MBT
They looked at embryonic gene expression (as a readout of MBT) in the cells with abnormal nuclei at different developmental stages.  The cells that had larger nuclei reached the critical nucleus to cytoplasm (N/C) ratio earlier in development and began expressing embryonic genes earlier than the neighboring cells with normal nuclei.  Likewise, the cells with smaller nuclei took a little bit longer than normal to undergo MBT.  I love that the two halves of the embryo are out of sync with each other just because the sizes of the nuclei are different.  This really shows that there is a critical N/C volume and manipulating this ratio is sufficient to initiate the midblastula transition.  

How do the cells know the size of the nucleus and cytoplasm?  The authors suggest that the oocyte must have inhibitors in it that repress transcription, so the embryo’s genome is inhibited at first.  As the cells divide, these inhibitors are split among them, so the inhibitors become less and less concentrated in each cell.  Once they reach a certain low concentration, they no longer function, so the cells can begin transcription.  This would explain why increasing nucleus size would cause an earlier midblastula transition: the larger nuclear volume essentially dilutes the inhibitor further, so it reaches that low threshold concentration sooner.  It’s important to get the timing of gene expression just right during development and the N/C volume appears to be one way that cells manage to do this.