tag:blogger.com,1999:blog-75503772403270111972024-02-07T18:00:35.742-08:00cellwaysA blog about current biology researchUnknownnoreply@blogger.comBlogger43125tag:blogger.com,1999:blog-7550377240327011197.post-10799581710563701502018-06-24T17:35:00.000-07:002018-06-24T17:35:36.893-07:00Too much phosphorylation, time to go to sleep!
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<span style="font-family: Arial;">It’s Friday night and you
are at a concert, wishing you hadn’t woken up at 4:45am to go to spin class. As
the night wears on you get more tired and fall asleep on the train ride home.
Why do you get tired the longer you stay awake? It’s not your muscles-- they
could keep contracting. There are chemical changes to molecules that accumulate
the longer we stay awake and they drive this need for sleep. This was shown in
a <a href="https://www.nature.com/articles/s41586-018-0218-8" target="_blank">recent paper in Nature</a> by Wang et al. using an interesting mouse mutant.</span></div>
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<b><i style="mso-bidi-font-style: normal;"><span style="font-family: Arial;">Sleepy</span></i><span style="font-family: Arial;">
mice</span></b></div>
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<span style="font-family: Arial;">When mice are sleep
deprived, they have an increased need for sleep (just like humans who get more
tired the longer they stay awake). Sleep need is measured by putting electrodes
on the mouse’s scalp that measure brain waves, which are large synchronized and
rhythmic patterns of electrical activity in the brain. When mammals sleep,
there are characteristic changes in the brain waves, so we can tell what stage
of sleep the animal is in. After sleep deprivation in mice, slow wave activity
and the duration of non-REM sleep increase, so this is used to measure sleep
need in mice. The researchers who did this study used sleep deprived mice, as
well as the <i style="mso-bidi-font-style: normal;">Sleepy</i> mutant mouse model
(I’m not being cute, this is the actual name of the mutant strain).</span></div>
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<span style="font-family: Arial;">The <i style="mso-bidi-font-style: normal;">Sleepy</i> mice have a mutation in a gene called <i style="mso-bidi-font-style: normal;">Sik3</i> that encodes for an enzyme. The mutation causes the enzyme to
work more efficiently and the mice sleep more, but have an elevated need for
sleep (as measured by the brain waves). So these mice are always tired due to
one amino acid change in one enzyme – that’s powerful.</span></div>
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<b><span style="font-family: Arial;">Phosphorylated proteins
drive sleep need</span></b></div>
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<span style="font-family: Arial;">The researchers compared
normal mice with the sleep deprived and <i style="mso-bidi-font-style: normal;">Sleepy
</i>mice, looking at the chemical changes to the proteins in their brains. The
sleep deprived and <i style="mso-bidi-font-style: normal;">Sleepy</i> mice had
more phosphorylated proteins than the mice who had a normal amount of sleep.</span></div>
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<span style="font-family: Arial;">Phosphorylated? That’s a
mouth full (<a href="http://howjsay.com/searchResult?word=phosphorylated" target="_blank">here’s how to say it</a>).
There is a small molecule called a phosphate, made up of a phosphorous atom
surrounded by oxygens. This chemical group is big and charged and will change
the shape of the rest of the protein when it is added on. Since phosphorylation
changes the shape of proteins, that may also change the way the proteins
function.</span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiISimw_ZJWG1oi_g9quEZRHREiaBazPMhNupff2oa0ojHY-TiDUwsp9UFLj0bx17vbRmNKynfkCJ58E2k4bl80eJw-LKfDdJgdkX_mhMjHYa6htu3fUjWRJAJQI6Z4b895PE_mMOwyy7Lc/s1600/Protein_conformation.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" data-original-height="528" data-original-width="570" height="370" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiISimw_ZJWG1oi_g9quEZRHREiaBazPMhNupff2oa0ojHY-TiDUwsp9UFLj0bx17vbRmNKynfkCJ58E2k4bl80eJw-LKfDdJgdkX_mhMjHYa6htu3fUjWRJAJQI6Z4b895PE_mMOwyy7Lc/s400/Protein_conformation.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Phosphorylation changes the shape of the protein (from Campbell's "Biology")</td><td class="tr-caption" style="text-align: center;"><br /></td><td class="tr-caption" style="text-align: center;"><br /></td></tr>
</tbody></table>
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<span style="font-family: Arial;"></span><span style="font-family: Arial;">The longer the sleep
deprived mice stay awake, the more phosphorylated proteins there are. If the
mice are allowed to sleep after being deprived, their proteins go back to the
unphosphorylated state. <i style="mso-bidi-font-style: normal;"> </i></span></div>
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<span style="font-family: Arial;"><i style="mso-bidi-font-style: normal;">Sleepy</i> mice
are always in need of sleep, regardless of how much sleep they get, so their
proteins are always phosphorylated. Why do <i style="mso-bidi-font-style: normal;">Sleepy</i>
mice have so many phosphorylated proteins? Remember that the <i style="mso-bidi-font-style: normal;">Sleepy</i> mice have a mutation that makes
the Sik3 enzyme more active. Guess what the function of Sik3 is! It is a kinase
enzyme, which adds phosphates to proteins. So the poor <i style="mso-bidi-font-style: normal;">Sleepy</i> mice accumulate phosphorylation at a higher rate than normal
mice, so they will always have an increased need for sleep.</span>
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi9VGivddx21AkK05Ct8h6pBbpPVPYNtg2egXbLhtvoMI88kqhMtw1Sug7_A4KRr2YmxojXrETi0Tigw5gKNJWhdePSgK3PIC8Cnpx3EHOrzTv4tFvYag71Bnru4TBxDQH_IU6BtRWpd2mM/s1600/mice+cartoon+small.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" data-original-height="518" data-original-width="1028" height="322" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi9VGivddx21AkK05Ct8h6pBbpPVPYNtg2egXbLhtvoMI88kqhMtw1Sug7_A4KRr2YmxojXrETi0Tigw5gKNJWhdePSgK3PIC8Cnpx3EHOrzTv4tFvYag71Bnru4TBxDQH_IU6BtRWpd2mM/s640/mice+cartoon+small.jpg" width="640" /></a></div>
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<span style="font-family: Arial;"><br /></span></div>
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<span style="font-family: Arial;"></span><span style="font-family: Arial;">Many of the proteins that
are being phosphorylated during the awake state function at the synapse, where neurons communicate with each other. Some neuroscientists believe that
memories are encoded while we are awake by changes to synaptic function. These
synaptic changes are refined during sleep to consolidate the memories in
long-term storage. The authors suggest that the accumulating phosphorylation
regulates synapse function and memory formation, though they don’t show
evidence for the connection with memory.</span>
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<span style="font-family: Arial;">In conclusion, next time you are getting
tired at that concert, just tell your friends, “My synaptic proteins are too
phosphorylated, I need to go home.” They’ll understand.</span></div>
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</style>Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-85720652602710305372018-06-24T17:15:00.004-07:002018-06-24T17:15:47.947-07:00Videos!<span style="font-family: Arial, Helvetica, sans-serif;">Cellways, it's been awhile! Here are a couple of videos I made in the last years:</span><br />
<br />
<br />
<span style="font-family: Arial, Helvetica, sans-serif;">A Ted-Ed video about X-chromosome inactivation and some interesting consequences of that. </span><br />
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<div class="separator" style="clear: both; text-align: center;">
<iframe width="320" height="266" class="YOUTUBE-iframe-video" data-thumbnail-src="https://i.ytimg.com/vi/veB31XmUQm8/0.jpg" src="https://www.youtube.com/embed/veB31XmUQm8?feature=player_embedded" frameborder="0" allowfullscreen></iframe></div>
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<span style="font-family: Arial, Helvetica, sans-serif;">A Science Sketches video about the basics of stem cell biology.</span><br />
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>
<div class="separator" style="clear: both; text-align: center;">
<iframe width="320" height="266" class="YOUTUBE-iframe-video" data-thumbnail-src="https://i.ytimg.com/vi/oAI6fBdp1JQ/0.jpg" src="https://www.youtube.com/embed/oAI6fBdp1JQ?feature=player_embedded" frameborder="0" allowfullscreen></iframe></div>
<span style="font-family: Arial, Helvetica, sans-serif;"><br /></span>Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-24551119464975379632016-12-30T20:59:00.000-08:002016-12-31T06:54:13.786-08:00Microbiome accelerates neurodegeneration<style>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">Parkinson
disease (PD) is a neurodegenerative disease characterized by motor deficits and
aggregates of a protein called </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;">-synuclein (</span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn)
in the brain (pronounced sin-NU-clee-in). Genetics plays a role in PD, because there are some early-onset
forms of PD that are caused by mutations in </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn that cause it to more readily clump together
and form the protein aggregates. The purely genetic forms of the disease,
though, are relatively rare, so the environment must also play a role in most
cases. <a href="http://www.cell.com/fulltext/S0092-8674(16)31590-2" target="_blank">A recent paper published in Cell</a> by Sampson et al. explores
how the microbiome in the gut affects development of PD symptoms.</span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">The
microbiome is the community of bacteria and fungi living in and on us (watch <a href="https://www.youtube.com/watch?v=5DTrENdWvvM" target="_blank">this awesome video</a> about the microbiome). It has
previously been shown that the normal gut microbiome is disrupted in various
diseases such as <a href="http://cellways.blogspot.com/2013/12/probiotics-for-autism.html" target="_blank">autism</a> and in Parkinson’s patients. It’s always hard to know, though, what is the
cause and what is the effect. Does the disease cause the microbiome to change,
or does the change in the microbiome cause the disease? Maybe a little of both.</span></div>
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<b><span style="font-family: "arial"; mso-bidi-font-family: Arial;">Mouse
model</span></b></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">To
address the role of the microbiome in Parksinson Disease, the authors relied on an established
mouse model of PD. These mice overexpress the normal human form of </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn in all their neurons.
Even though this isn’t the mutant form of the gene, the fact that it is
overexpressed all over the brain causes the characteristic </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "symbol"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn aggregates. These
mice are slow in motor tasks, including removing a piece of tape from their noses
(sounds like a frustrating, but also <a href="https://www.youtube.com/watch?v=mYL1wZsiHsM" target="_blank">adorable behavioral task</a>).
They also have impaired gastrointestinal function, which is to say they don’t
produce as much poo as other mice. [An aside: normal mice apparently drop about
7 fecal pellets every 15 minutes!]</span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">The
researchers took these mice with mouse-Parkinson’s and raised half of them in a
super sterile environment where they have no microbiome (called “germ free”
mice), and the other half got all dirty so they had a microbiome (I will call
these “dirty mice”). The PD mice with a microbiome had way more motor
impairments than the mice without a microbiome! Yes, I wrote that correctly. I
thought the microbiome was supposed to help its host? Well, not in these mice
overexpressing </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn.</span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">Get
this: if you give the dirty mice antibiotics from age 5-13 weeks old and then
test them, they were more like the germ free mice – no motor impairments and
better fecal output. Not that you would want to give humans antibiotics for
their entire lives (that could cause some autoimmune diseases and serious
digestive issues), but this does demonstrate that it is the gut microbiome that
is affecting the symptoms of Parkinson Disease.</span></div>
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<b><span style="font-family: "arial"; mso-bidi-font-family: Arial;">Short
chain fatty acids</span></b></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">The
bacteria living in our gut produce all sorts of chemicals that can get into our
blood and nervous system. Bacteria produce short-chain fatty acids (SCFA),
which are basically just little fats that can cross over the intestinal lining
and get into our bodies. Parkinson’s patients produce more SCFAs, so the
authors tested the role of SCFAs in their mouse model. </span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">Germ
free mice overexpressing </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "symbol"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn
are relatively normal, right? The authors fed these mice a bunch of SCFAs to
mimic what the gut bacteria would be making and the mice became impaired like
the dirty mice (can’t get that tape off their nose). This is amazing to me. So
short-chain fatty acids that are normally made by the gut bacteria are
sufficient to cause the Parkinson’s symptoms. Note that feeding SCFAs to normal mice without all that </span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "symbol"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span>-syn did not cause Parkinson's symptoms.</span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;"><span style="mso-tab-count: 1;"> </span></span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "symbol"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn mice no microbiome + SCFAs = impairments
of </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "symbol"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn mice with microbiome</span></div>
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<b><span style="font-family: "arial"; mso-bidi-font-family: Arial;">Microbiome
and the immune system</span></b></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">What
are the short-chain fatty acids doing to the nervous system? One important role
of the microbiome is to train the host’s immune system so it knows what to
attack and what to ignore. This is why the microbiome plays a role in the
development of autoimmune diseases, where the body attacks the wrong things
(like a harmless pollen molecule or the body’s own cells like in type I
diabetes). SCFAs can get up into the brain and regulate the immune cells of the
nervous system, called the microglia (pronounced micro-GLEE-a). Indeed, the dirty mice with a full microbiome
had more activated microglia in the brain than the germ free mice. Likewise,
the germ free mice fed SCFAs also had activated microglia.</span></div>
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">An
overactive immune system promotes protein aggregation, so here’s the model:
something causes the microbiome to become unhealthy, which causes the release
of a lot of SCFAs, which activate the immune system in the brain, leading to
neuron death and protein aggregation. The diagram below has some extra
information in it, but the pathway in black is what they showed in this paper.</span></div>
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgcrD8D8gEbEUg6jCn32rin3MR23g12cIqAZT7MWcRshiFQrxjuBLla4OZDUXknLBa4p5ZwkUvavyuwPpdJ7Ag0NZGSf5z6hJ4Mf5stnob-u6A65GXfWoHkPiYp8F_t4QxlzARkTWmUU06/s1600/161230+summary+diagram+Newest.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="432" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEhgcrD8D8gEbEUg6jCn32rin3MR23g12cIqAZT7MWcRshiFQrxjuBLla4OZDUXknLBa4p5ZwkUvavyuwPpdJ7Ag0NZGSf5z6hJ4Mf5stnob-u6A65GXfWoHkPiYp8F_t4QxlzARkTWmUU06/s640/161230+summary+diagram+Newest.jpg" width="640" /></a></div>
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<br />
<b><span style="font-family: "arial"; mso-bidi-font-family: Arial;">What
about human patients?</span></b><b>
</b><br />
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<span style="font-family: "arial"; mso-bidi-font-family: Arial;">Okay,
so the microbiome plays a role in this one particular mouse model of PD, but
what about in humans? Remember that the microbiome and the amount of short-chain fatty acids in
Parkinson’s patients are different than in healthy humans. The authors took the
microbes from human feces and transplanted it into the guts of the germ free </span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">α-syn mice. Amazingly, the germ free mice that got the bacteria from Parkinson’s
patients had more severe motor impairments than the mice that got bacteria from
the healthy humans. So there’s something going on in the microbiome of humans
with PD that enhances the symptoms. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial"; mso-bidi-font-family: Arial;">The
authors raise the point that two things were needed for these mice to have the
symptoms of Parkinson disease:</span></div>
<div class="MsoNormal">
<span style="font-family: "arial"; mso-bidi-font-family: Arial;">1)
Overexpression of </span>α<span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;">-syn
(genetics)</span></div>
<div class="MsoNormal">
<span style="font-family: "arial"; mso-bidi-font-family: Arial;">2)
Disordered microbiome, also known as dysbiosis (environment)</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial"; mso-bidi-font-family: Arial;">This
is a great example of a complex disease that is caused by the interplay of
genetics and environment. Perhaps this information can be used to come up with
new treatments to correct the dysbiosis and slow down the progression of
Parkinson disease.</span><span style="font-family: "arial"; mso-bidi-font-family: Arial;"></span><span style="font-family: "arial"; mso-bidi-font-family: Arial;"> </span>
</div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-58963076156913553712016-09-04T13:55:00.000-07:002016-09-04T17:35:17.237-07:00Human language in dog brains<style>
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<div class="MsoNormal">
<span style="font-family: "arial";">Spoken language conveys
meaning in two ways: the meaning of the words (semantics or lexical knowledge) and the intonation
that the speaker uses. We can sense questions by the rising pitch at the end of
the sentence. Likewise, we can tell if someone is upset or being sarcastic based
on how they say the words. The patterns of intonation in language is known as
prosody. There are areas of the brain that are specialized for decoding the
semantic meaning of language and <u>different areas</u> for interpreting prosody.
In fact, you can have damage to one area during a stroke, while the other area
remains intact. There are great examples of this in <a href="http://www.indiana.edu/~jkkteach/P335/PresidentsSpeech.html" target="_blank">“The President’s Speech”</a> in
Oliver Sacks' book <i style="mso-bidi-font-style: normal;">The Man who Mistook his Wife for a Hat</i>. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">In most people, word
meanings are processed by the left side of the brain and prosody is localized
to the right side of the brain. Some animals also use the left side of their
brains to understand meaningful and familiar sounds of their species (like
alert calls or bird songs). What about for animals, like dogs, which can
understand the sounds of another species (i.e. commands from humans). Is the
dog brain really processing the intonations of praise “good dog!” or are they
responding to the words? Do they process meaning and intonation separately like
humans do?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: "arial";">Dogs in MRI machines</span></b></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">In the latest issue of
Science, <a href="http://science.sciencemag.org/content/early/2016/08/26/science.aaf3777" target="_blank">Andies et al. published </a>their studies of language processing in dog
brains. My first thought when I read the abstract was “how do you get a dog
into an MRI machine?” We commonly study which areas of human brains are active
during different tasks using a technique called functional MRI (or fMRI). fMRI
was done on these dogs while they listened to their trainers speak. If you have
ever had an MRI scan, you know they strap you in and you cannot move your head
at all. Same thing with these dogs. Needless to say, they were very well
trained dogs. If you still can’t believe it, <a href="https://www.youtube.com/watch?v=N9QQxa6eLPc" target="_blank">check out this video</a> the
researchers made and the cute photo of dogs in an MRI machine below.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh0EPMotcADbMPVvno5WiZDAs3jcgEQYleIuNcZAr6y-HRCqsz-wPxvhyphenhyphenqQpX-zmd3rKJMibbmSfj8XEq9WiVwvIZ3LVcJ_yp7460m-pVEFQ43TR4NQI0kM5wEYKhURpy03elvhhmdJSg6Q/s1600/2-dogsundersta.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="240" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh0EPMotcADbMPVvno5WiZDAs3jcgEQYleIuNcZAr6y-HRCqsz-wPxvhyphenhyphenqQpX-zmd3rKJMibbmSfj8XEq9WiVwvIZ3LVcJ_yp7460m-pVEFQ43TR4NQI0kM5wEYKhURpy03elvhhmdJSg6Q/s400/2-dogsundersta.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Really well trained dogs lying still before their MRIs. <a href="http://phys.org/news/2016-08-dog-brains.html" target="_blank">(Image from phys.org)</a></td></tr>
</tbody></table>
<div class="MsoNormal">
<b><span style="font-family: "arial";">Dogs process language like
humans</span></b></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">Okay, so they got the dogs
in the MRI machine and scanned their brains while they heard their trainer say
different things. The trainer would either say words of praise, like “good boy” (in Hungarian),
or neutral words. And they used either a neutral, flat intonation or they
raised the pitch of their voice to create a praising intonation. This created
four possibilities: </span></div>
<ul>
<li><span style="font-family: "arial";">Praise words with praising
intonation</span></li>
<li><span style="font-family: "arial";">Praise words with neutral
intonation</span></li>
<li><span style="font-family: "arial";">Neutral words with praising
intonation</span></li>
<li><span style="font-family: "arial";">Neutral words with neutral
intonation</span></li>
</ul>
<div class="MsoNormal">
<span style="font-family: "arial";">They compared the brain
responses to each combination and found that the <i style="mso-bidi-font-style: normal;">left</i> side of the brain responded to words of praise regardless of
the intonation. This is amazing, right? The dogs have heard “good boy” enough
times that their brains responded specifically to that phrase regardless of how it was said. It’s like they
sort of know what it means. It would be interesting to see if they respond to the same phrase spoken by a stranger.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">The researchers also found that the <i style="mso-bidi-font-style: normal;">right</i> side of the brain had active areas
when praising intonation was used, regardless of the word meaning. So dogs also
understand how our voices change when we praise them. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">Finally, the researchers
looked at areas of the brain associated with reward. These areas are active in
a variety of animals when they receive natural rewards like food or during sex,
but the <a href="http://cellways.blogspot.com/2013/01/isolation-and-drug-addiction.html" target="_blank">reward pathways</a> are also active if the animal is given an addictive drug like cocaine.
Alternatively, you can put an electrode into a mouse brain that stimulates the
reward pathway and the mouse will push a lever to receive an electrical shock
in this area of the brain over and over until it starves. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">Andies et al. found that praising
words spoken in a praising intonation activated the reward pathway in the dogs.
Praise words alone and praise intonation alone had no effect. So dogs really do
feel good when you say “good dog” in a high pitched voice.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">Notice the organization of
language processing in the dog brain. Just like in humans, language semantics
(praise vs neutral words) was processed on the left side and prosody (praise vs
neutral intonation) was processed on the right side. What does this tell us
about the evolution of language? Language lateralization has likely been around
a long time and is not uniquely human. The authors end the article with this
gem: “What makes lexical items uniquely human is thus not the neural capacity
to process them, but the invention of using them.”</span></div>
Unknownnoreply@blogger.com2tag:blogger.com,1999:blog-7550377240327011197.post-77073875988658336252016-05-21T18:43:00.001-07:002016-05-21T18:44:56.129-07:00No Y genes? No problem, bro.<style>
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<div class="MsoNormal">
<span style="font-family: "arial";">The Y-chromosome is one of
the smallest chromosomes in the human genome and contains genes involved in
male development and production of sperm. Previous research has shown that just
two genes on the Y chromosome are necessary to make male mice who can sort of
produce sperm. By “sort of” I mean that the mice make things called “round
spermatids”, which genetically are the same as sperm, but are underdeveloped,
so they can’t naturally fertilize an egg. A lab in Hawaii took these round
spermatids and injected them into oocytes to demonstrate that the resulting
zygotes are viable and develop into normal mice. In other words, the
experimental mice have only one X chromosome and the two Y genes, and they
develop into males who can reproduce with a little help from scientists.<span style="mso-spacerun: yes;"> </span>That is pretty amazing that only two genes
can make a male.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: "arial";">The necessary Y genes</span></b></div>
<div class="MsoNormal">
<span style="font-family: "arial";"></span><span style="font-family: "arial";">So what are these two genes?
One of them is called Sry, which encodes for a transcription factor that
regulates expression of other genes important for the development of the male
reproductive system (see the figure below). The other necessary gene is Eif2s3y, which is involved in
protein synthesis and somehow necessary for the production of sperm. There is a similar gene on the X-chromosome, which may
serve the same function. Normal XY males express both Eif2s3y and Eif2s3x, the
version on the X-chromosome.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiixBGmgwKIX_XzhutVigg2BIQJOTpwzd0EYzfrw__MtayNSAJOORJ3zjP6zGzqvsTKLPTdMB8weE0lFfVgq5RuqI9tg9qQjcrCrB5w6r6MD14d8bC6qwoX4dcoE4-rkfCkk3uF0UwmOVQd/s1600/Sry+function+small.png" imageanchor="1"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiixBGmgwKIX_XzhutVigg2BIQJOTpwzd0EYzfrw__MtayNSAJOORJ3zjP6zGzqvsTKLPTdMB8weE0lFfVgq5RuqI9tg9qQjcrCrB5w6r6MD14d8bC6qwoX4dcoE4-rkfCkk3uF0UwmOVQd/s1600/Sry+function+small.png" /></a> </span>
</div>
<div class="MsoNormal">
<span style="font-family: "arial";">In a paper that came out
<a href="http://science.sciencemag.org/content/351/6272/514" target="_blank">earlier this year in Science</a>, Yamauchi et al. asked whether they could replace
the function of Sry and Eif2s3y with other genes that are found on other
chromosomes. Instead of a male mouse with Eif2s3y, what if you made a mouse
that was overexpressing Eif2s3x?<span style="mso-spacerun: yes;"> </span>Could
the X version compensate for the Y version? And instead of Sry, could you
overexpress one of its target genes to replace its function?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">Through the power of mouse
genetics, the researchers created a mouse line with one X-chromosome and no Y-chromosome,
which overexpressed Eif2s3x and Sox9, one of the Sry targets. In other words, these mice do not have any genes that are normally found on the Y-chromosome.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: "arial";">A male mouse with no Y</span></b></div>
<div class="MsoNormal">
<span style="font-family: "arial";">The mice with no
Y-chromosomes and no Y genes, but overexpression of Sox9, developed into males,
with male reproductive systems (though smaller and less developed). When
Eif2s3x was overexpressed along with Sox9, the males were able to produce the
round spermatids (precursors for sperm). The researchers did their artificial
fertilization with these round spermatids and were able to produce healthy
offspring. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUEXJsvvufUZScw8f11PuOfYtahFYF7Oq1r2dW2vmmDH8c_qR1Bv6MvaLp_v-Um1BUNsTwItbsMqFJ7FAtGMs9ll6JGGxsIOPqd20Pm_Qi10ok2sdWVgel1EsY2xVtKmjXic0O8ZMjXPVv/s1600/Expt+results+small.png" imageanchor="1"><img border="0" height="154" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjUEXJsvvufUZScw8f11PuOfYtahFYF7Oq1r2dW2vmmDH8c_qR1Bv6MvaLp_v-Um1BUNsTwItbsMqFJ7FAtGMs9ll6JGGxsIOPqd20Pm_Qi10ok2sdWVgel1EsY2xVtKmjXic0O8ZMjXPVv/s640/Expt+results+small.png" width="640" /></a> </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: "arial";">So just to repeat: the mice
without a single gene from the Y-chromosome developed into males and produced
sperm that are good enough for successful in vitro fertilization. Just by
overexpressing two genes found on other chromosomes. That’s amazing!</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-73243417296955851532015-07-19T17:18:00.000-07:002015-07-19T17:18:09.542-07:00Pandas are lazy!
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<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Pandas are closely related to carnivorous
mammals (like all the other bears), but they consume mostly bamboo.<span style="mso-spacerun: yes;"> </span>Their digestive tracts are short and adapted
for digesting meat, not cellulose that is found in plants.<span style="mso-spacerun: yes;"> </span>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)!<span style="mso-spacerun: yes;"> </span>How are these large, adorable bears able to
get enough energy to function from their inefficient digestion of bamboo?<span style="mso-spacerun: yes;"> </span>Researchers in China and Scotland addressed
this question by studying captive and wild pandas, <a href="http://www.sciencemag.org/content/349/6244/171" target="_blank">described in a recent Science article</a>.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Low energy expenditure</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">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.<span style="mso-spacerun: yes;"> </span>In fact, pandas are expending energy at
levels similar to the three-toed sloth, the epitome of a low-energy
mammal.<span style="mso-spacerun: yes;"> </span>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.</span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">How do the pandas manage to spend so little
energy?<span style="mso-spacerun: yes;"> </span>There must be some adaptations
that are allowing the panda to survive without expending so much energy.<span style="mso-spacerun: yes;"> </span>The authors found a number of these
adaptations:</span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">1) Pandas have a thick layer of fur, so they
can maintain their internal body temperature with less heat loss through the
skin.<span style="mso-spacerun: yes;"> </span>The researchers measured
temperature at the surface of various animals and the pandas consistently were
cooler than other mammals (like a cow or dog).<span style="mso-spacerun: yes;">
</span>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.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">2) Pandas are lazy.<span style="mso-spacerun: yes;"> </span>No surprise: pandas spend more time inactive
and when they do move, it is slowly.<span style="mso-spacerun: yes;"> </span>So
that is less energy needed for muscle contractions.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">3) Pandas have small brains, livers and
kidneys, so their organs need less energy.</span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">4) Pandas have a low resting metabolic rate,
which is driven by the thyroid hormones, T3 and T4.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>The thyroid
hormones regulate protein, carbohydrate and fat metabolism, as well as growth
and development.<span style="mso-spacerun: yes;"> </span>If the pandas don’t
need to produce as much heat or energy, then there is no reason to have a high
metabolic rate. </span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Interestingly, pandas have a single mutation in
a gene called <i>DUOX2</i>, which is not found in any other mammals.<span style="mso-spacerun: yes;"> </span><i>DUOX2</i> encodes for a protein that is necessary
for the production of T3 and T4.<span style="mso-spacerun: yes;"> </span>The
mutation causes a premature “stop” in the protein, so it likely affects the
function of DUOX2.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">In other words, pandas cannot synthesize T3 and
T4 as well because of this mutation, so they have a reduced metabolic
rate.<span style="mso-spacerun: yes;"> </span>But that’s okay, because they are
good at maintaining their body temperature and they have developed an enjoyable
lifestyle of relaxing and eating.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>So it all works out: pandas are
able to survive on their diet of bamboo and we can watch them sit around.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-16035237813143050502015-03-22T17:50:00.002-07:002015-03-22T21:01:15.169-07:00Bigger brains with Frizzled HARE<style>
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<span style="font-family: Arial;">We have all heard that the
sequence of human DNA differs from chimpanzee DNA by only about 1%.<span style="mso-spacerun: yes;"> </span>Yet humans are capable of building complex
civilizations while the chimps are still eating bugs in the forest.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiILpdVFG9f_9IQd8aylcKSATjDjechgtYJdSRVkwaVA0jeE9-vCr5PsdLaOPxQ82v8ErgjPW1-K5v6cJcKEByzlh7dKa_89_csRHj4W9mkHLGIR_SDxVBRJ3yfxU3Oo17zda4drjWVOCGJ/s1600/a_05_cr_her_1a.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiILpdVFG9f_9IQd8aylcKSATjDjechgtYJdSRVkwaVA0jeE9-vCr5PsdLaOPxQ82v8ErgjPW1-K5v6cJcKEByzlh7dKa_89_csRHj4W9mkHLGIR_SDxVBRJ3yfxU3Oo17zda4drjWVOCGJ/s1600/a_05_cr_her_1a.jpg" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">From thebrain.mcgill.ca</td></tr>
</tbody></table>
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<br /></div>
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<span style="font-family: Arial;">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?<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;">
</span>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. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><a href="http://www.cell.com/current-biology/abstract/S0960-9822%2815%2900073-1" target="_blank">A recent paper in Current Biology</a> by Boyd et al. explores these questions by studying a human-accelerated regulatory
enhancer (HARE5), which differs significantly between humans and chimps.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Enhancer activity of HARE5</span></b></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">How do you study
enhancers?<span style="mso-spacerun: yes;"> </span>One way is to use a reporter
gene.<span style="mso-spacerun: yes;"> </span>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?<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>The enhancers from the chimps and humans
drove expression of the reporter gene in the embryonic mouse brains.<span style="mso-spacerun: yes;"> </span>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).</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgb8XQXRAwTicl0VLyXeZ12UdouiQGAZhaYpJIV_-z6xBXYPh6V-ykIv81vkM6Sn6mPccILcK2r6AYC33x5ek9W9FICl2UgfZl9pyKI9hym7JZK6bXoe_Zr5mUdvp-eys655PWoqWawIVDu/s1600/Boyd+experiment.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgb8XQXRAwTicl0VLyXeZ12UdouiQGAZhaYpJIV_-z6xBXYPh6V-ykIv81vkM6Sn6mPccILcK2r6AYC33x5ek9W9FICl2UgfZl9pyKI9hym7JZK6bXoe_Zr5mUdvp-eys655PWoqWawIVDu/s1600/Boyd+experiment.png" height="428" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Reporter gene experiment. The mouse brain images are actual results from Figure 2 in Boyd et al. (2015).</td></tr>
</tbody></table>
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<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">This tells us that whatever
normal gene is near HARE5, it is probably expressed earlier and way more in
humans than in chimps.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Frizzled expression is
regulated by HARE5</span></b></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">So which genes are near the
HARE5 sequence?<span style="mso-spacerun: yes;"> </span>The closest gene is
called Frizzled 8 and it is a receptor that responds to signals sent by other
cells.<span style="mso-spacerun: yes;"> </span>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).<span style="mso-spacerun: yes;"> </span>The authors demonstrate that the mouse HARE5
physically interacts with Fzd8, which is a necessary<span style="mso-spacerun: yes;"> </span>first step of gene expression, so Fzd8 is
likely affected by the HARE5 sequence differences in humans and chimps.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">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.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>They injected these DNA
constructs into mice and waited to see what would happen to embryonic brain
development.<span style="mso-spacerun: yes;"> </span>When the chimp-HARE5 was
driving expression of Fzd8, not much changed in terms of mouse brain
development.<span style="mso-spacerun: yes;"> </span>However, when the
human-HARE5 sequence was activating the mouse Fzd8 gene, the mouse brain grew
12% bigger!!<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Let me be clear here-- they are not expressing the human Fzd gene in
mice.<span style="mso-spacerun: yes;"> </span>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).<span style="mso-spacerun: yes;"> </span>The neural progenitor cells
(pre-neurons) divided faster than in a normal mouse, leading to formation of
more neurons, and a bigger brain!<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">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.<span style="mso-spacerun: yes;"> </span>Whoa.<span style="mso-spacerun: yes;"> </span>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.</span></div>
<div class="MsoNormal">
<br /></div>
<span style="font-family: Arial; font-size: 12.0pt; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "MS 明朝"; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-fareast;">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.</span><br />
<br />
<a href="http://www.molecularecologist.com/2015/02/this-is-your-brain-on-human-accelerated-regulatory-enhancer-hare5/" target="_blank"><span style="font-family: Arial; font-size: 12.0pt; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "MS 明朝"; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-fareast;">Here's another blogger's take on this paper</span></a><span style="font-family: Arial; font-size: 12.0pt; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "MS 明朝"; mso-fareast-language: EN-US; mso-fareast-theme-font: minor-fareast;"> </span>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-83582776043541391492015-01-11T17:50:00.000-08:002015-01-11T18:23:08.600-08:00Smart phone use changes the brain<style>
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<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-eA77_vebkVtI3iGc-vN7cvpWOTmsShKIS_jBM1jcR5noOOkq8Lp6r95Lpg8HJLz6FlfbaETQZMlgrElb24w3TvdbgLn4Oi2DRSav_l56F69TOH7U4XRxjD-7eA8CGgibSn1iDHTqKRfG/s1600/sensory+cortex.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg-eA77_vebkVtI3iGc-vN7cvpWOTmsShKIS_jBM1jcR5noOOkq8Lp6r95Lpg8HJLz6FlfbaETQZMlgrElb24w3TvdbgLn4Oi2DRSav_l56F69TOH7U4XRxjD-7eA8CGgibSn1iDHTqKRfG/s1600/sensory+cortex.jpg" height="262" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Functional organization of brain cortex. (Source: imgarcade.com/1/sensorycortex)</td></tr>
</tbody></table>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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 href="http://www.cell.com/current-biology/abstract/S0960-9822%2814%2901487-0" target="_blank">A recent paper by Gindrat et al.</a> addressed this exact question using EEG to record brain
activity in smart phone users versus people with the old-style cell phones.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: Arial;">Electroencephalography</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLvdMc0_yb_RU6UkSlNPmoAymXwtgWPEOWjUvL9G_GADK1SgnZLgkcWbEJF3o-RqrETIAWEOxBmtgDFNKafZQvojmgsL8pnftzaR1VoyDL46R9wdfuvhNBsr218RWS5wWwscmMtd5ye6zd/s1600/640px-EEG_recording.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgLvdMc0_yb_RU6UkSlNPmoAymXwtgWPEOWjUvL9G_GADK1SgnZLgkcWbEJF3o-RqrETIAWEOxBmtgDFNKafZQvojmgsL8pnftzaR1VoyDL46R9wdfuvhNBsr218RWS5wWwscmMtd5ye6zd/s1600/640px-EEG_recording.jpg" height="238" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">EEG electrodes record brain activity (source: Wikimedia commons)</td></tr>
</tbody></table>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: Arial;">Finger
representations in smart phone users</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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). </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">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.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-21199943466351420542015-01-05T22:00:00.000-08:002015-01-11T18:15:12.533-08:00What big nuclei you have!<style>
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<br />
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Eggs get ready for fertilization by producing
and storing all the proteins necessary for early embryo development.<span style="mso-spacerun: yes;"> </span>After fertilization, there are a series of
rapid cell divisions without growth, producing a lot of small cells <a href="https://www.youtube.com/watch?v=28GTvrNvRRE" target="_blank">(here's a video)</a>.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>This transition
to embryonic transcription is known as the midblastula transition, or MBT.<span style="mso-spacerun: yes;"> </span>How does the embryo know when it is time to
turn on gene expression?<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">One theory is that the ratio of nuclear to
cytoplasmic volume (N/C volume) is the trigger for MBT.<span style="mso-spacerun: yes;"> </span>The nucleus is where DNA is stored within a
cell; this is where gene expression occurs.<span style="mso-spacerun: yes;">
</span>The cytoplasm is the goo that the nucleus sits in.<span style="mso-spacerun: yes;"> </span>During those rapid early cell divisions,
nucleus size does not change much, while the cytoplasm in each cell keeps
getting smaller and smaller.<span style="mso-spacerun: yes;"> </span>The N/C
volume increases, since the cytoplasmic volume is decreasing.<span style="mso-spacerun: yes;"> </span>Is there a certain threshold of N/C volume,
above which the embryo switches on gene expression?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQSGTdXczaKxUWIgNIQBlRB6uKdz3zSK_rdT1zd5Z0s40yqVv8-_2GV2ZjwxAcBKGubwAHDfiiQ8g8g6FTtUTHtb_oYmnxstInumzGwqD-QPlj5wF0LVMAywOe58xQhMVXBlXb68LvoBOp/s1600/Cell+division.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgQSGTdXczaKxUWIgNIQBlRB6uKdz3zSK_rdT1zd5Z0s40yqVv8-_2GV2ZjwxAcBKGubwAHDfiiQ8g8g6FTtUTHtb_oYmnxstInumzGwqD-QPlj5wF0LVMAywOe58xQhMVXBlXb68LvoBOp/s1600/Cell+division.png" height="148" width="400" /></a></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Jevtic and Levy did a series of clever
experiments, using frog embryos to address this question, which was <a href="http://www.cell.com/current-biology/abstract/S0960-9822%2814%2901360-8" target="_blank">published today in Current Biology</a>.<span style="mso-spacerun: yes;"> </span>In <i style="mso-bidi-font-style: normal;">Xenopus laevis</i> frogs, the midblastula
transition always occurs after the 12<sup>th</sup> cell division.<span style="mso-spacerun: yes;"> </span>The researchers manipulated the nucleus size
in the frog embryos to see if that would change the timing of MBT.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">Changing nuclear volume</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">The authors were able to increase nucleus
volume by injecting embryos with mRNA for importin and a type of lamin. <span style="mso-spacerun: yes;"> </span>Importin acts as a shuttle that brings other
proteins into the nucleus, including structural proteins that make up the
nuclear envelope.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>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.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">They injected the mRNAs and a red dye into one
cell in the two-cell stage.<span style="mso-spacerun: yes;"> </span>When this
cell divides, its daughter cells inherit the red dye and the mRNAs and proteins
that change the nucleus size.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<b>
</b><br />
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">N/C volume triggers MBT</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">They looked at embryonic gene expression (as a
readout of MBT) in the cells with abnormal nuclei at different developmental
stages.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>Likewise, the cells with smaller nuclei took
a little bit longer than normal to undergo MBT.<span style="mso-spacerun: yes;">
</span>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.<span style="mso-spacerun: yes;"> </span>This really shows that there is a critical
N/C volume and manipulating this ratio is sufficient to initiate the
midblastula transition.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGRM5Cr9ttIAuVzvtqJduyU7cgIGRYKdc1Xy3Eu9BPeUftiOxDKQCV_RazY8ajEM-xKg3DkAqhNBhFuWCVvUaEO6h_bwiKENlQPwIVp_o9GF2Ya1eg_7IljxrxoP7uS0ZoOKxvo-lqrH90/s1600/results.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgGRM5Cr9ttIAuVzvtqJduyU7cgIGRYKdc1Xy3Eu9BPeUftiOxDKQCV_RazY8ajEM-xKg3DkAqhNBhFuWCVvUaEO6h_bwiKENlQPwIVp_o9GF2Ya1eg_7IljxrxoP7uS0ZoOKxvo-lqrH90/s1600/results.png" height="297" width="640" /></a></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman"; mso-bidi-theme-font: minor-bidi;">How do the cells know the size of the nucleus
and cytoplasm?<span style="mso-spacerun: yes;"> </span>The authors suggest that
the oocyte must have inhibitors in it that repress transcription, so the
embryo’s genome is inhibited at first.<span style="mso-spacerun: yes;">
</span>As the cells divide, these inhibitors are split among them, so the
inhibitors become less and less concentrated in each cell.<span style="mso-spacerun: yes;"> </span>Once they reach a certain low concentration,
they no longer function, so the cells can begin transcription.<span style="mso-spacerun: yes;"> </span>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.<span style="mso-spacerun: yes;"> </span>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.</span></div>
Unknownnoreply@blogger.com2tag:blogger.com,1999:blog-7550377240327011197.post-17885042244157869102014-11-29T15:15:00.001-08:002014-11-29T15:15:36.116-08:00Improving reproductive cloning
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<div class="MsoNormal">
<span style="font-family: Arial;">Remember when Dolly the
sheep was cloned in 1996?<span style="mso-spacerun: yes;"> </span>That was the
first cloned mammal and everyone freaked out thinking we would be cloning all
our pets and even humans within a few years.<span style="mso-spacerun: yes;">
</span>Well, nearly 20 years have passed since then and reproductive cloning is
still a very difficult and inefficient procedure.<span style="mso-spacerun: yes;"> </span>Most cloning has a 1-5% success rate.<span style="mso-spacerun: yes;"> </span>Why is that?<span style="mso-spacerun: yes;">
</span>Before we can answer that, we need to understand the procedure for
reproductive cloning.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Somatic cell nuclear
transfer</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Our bodies are made up lots
of different types of cells – neurons, skeletal muscle, intestinal cells,
immune cells, etc.<span style="mso-spacerun: yes;"> </span>Despite the different
functions and structures of these cells, all of the cells in one organism have
the same genome, the same set of genes.<span style="mso-spacerun: yes;">
</span>What makes cells unique is that they express different genes at
different times, so different proteins are made.<span style="mso-spacerun: yes;"> </span>What this means is that the blueprint (DNA) for
making a new organism is right there in every cell in your body.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The normal way of making an
embryo is by taking half of the genome from a male (in sperm) and half from a
female (in the egg) and combining them during fertilization.<span style="mso-spacerun: yes;"> </span>In reproductive cloning, you already have a
whole genome from any adult cell.<span style="mso-spacerun: yes;"> </span>That
nucleus from the adult can be inserted into an oocyte (or egg) that has had its
DNA removed (“enucleated”).<span style="mso-spacerun: yes;"> </span>The egg is
necessary because it has lots of nutrients and signals in it that are important
for the first few cell divisions during early development.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">This process is shown in the
diagram below and is called somatic cell nuclear transfer.<span style="mso-spacerun: yes;"> </span>In the example, the adult genome is coming
from a fibroblast cell and is transferred into an enucleated oocyte.<span style="mso-spacerun: yes;"> </span>This is a way to get stem cells (ntES), which
can be used for therapeutic purposes, like making more neurons that can be
transplanted into someone with Parkinson’s.<span style="mso-spacerun: yes;">
</span>Or you could let the cloned cells grow up into an embryo and then into a
cloned organism.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_Z7l9rW71Eai2NGwWRsJ3NU0s3el_eA33q3irAKZsjBFQSuau3AGuEDYqfVHCimEKn_-zubwwzONzRXj69IpbG9652c4wPKlg5fjQFPXoLiK8ci3opvzDKLOc5H6mzy-yQjQVDbydNnHa/s1600/SCNT.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh_Z7l9rW71Eai2NGwWRsJ3NU0s3el_eA33q3irAKZsjBFQSuau3AGuEDYqfVHCimEKn_-zubwwzONzRXj69IpbG9652c4wPKlg5fjQFPXoLiK8ci3opvzDKLOc5H6mzy-yQjQVDbydNnHa/s1600/SCNT.png" height="155" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Somatic nuclear cell transfer (from Stembooks.org)</td></tr>
</tbody></table>
<div class="MsoNormal">
<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Although it is possible to
make cloned organisms using adult donor genomes, the efficiency is much higher
when using genomes from embryos.<span style="mso-spacerun: yes;"> </span>What
happens to the adult genome that prevents it from directing the formation of a
new organism?<span style="mso-spacerun: yes;"> </span>This problem is addressed
in a recent paper by <a href="http://www.cell.com/cell/abstract/S0092-8674%2814%2901243-4" target="_blank">Matoba et al., published in Cell</a>.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Epigenetic changes</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Although adult cells should
have the same DNA sequences as their embryonic precursors, the genome can be
organized differently, which can affect which genes are expressed.<span style="mso-spacerun: yes;"> </span>DNA wraps around histone proteins as a way to
organize the long DNA chains.<span style="mso-spacerun: yes;"> </span><a href="http://www.cellways.blogspot.com/2012/03/take-two-hdac-inhibitors-and-call-me-in.html" target="_blank">Histones can be modified</a> in such a way that the DNA will wrap around more tightly or
more loosely.<span style="mso-spacerun: yes;"> </span>For example, if a
particular amino acid in histone 3 is trimethylated (three CH3 groups are
added), then that makes the DNA pack up closer together, so it is really hard to
express those genes.<span style="mso-spacerun: yes;"> </span>There are genes
that may need to be expressed early on in development, so their histones will
be modified to allow for loose packing, but then after they are expressed,
they’ll get packed away, so they take up less space.<span style="mso-spacerun: yes;"> </span>These kinds of modifications that affect gene
expression are called epigenetics.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">As an analogy, imagine you
have had a child, so you have baby clothes, a crib, car seat and toys in your
house.<span style="mso-spacerun: yes;"> </span>Once that child grows up, you
take all those baby things down to the basement.<span style="mso-spacerun: yes;"> </span>You still have them, but you will probably
never need to use them again, so you can pack them all up and store them so
they are out of the way.<span style="mso-spacerun: yes;"> </span>It may be hard
to access them again, but they are still there.<span style="mso-spacerun: yes;">
</span>So a gene that has been packed away into condensed chromatin is still
present in a cell, but it is no longer giving instructions for making proteins,
unless something comes along and unpacks it.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">You can see now the problem
with somatic cell nuclear cloning.<span style="mso-spacerun: yes;"> </span>The
adult cell already has some DNA packed away, so when the genome is put into an
oocyte, it may be impossible to express the genes necessary to direct normal
development.<span style="mso-spacerun: yes;"> </span>In the paper by Matoba et
al., they did indeed find that there are more trimethyl modifications (called
H3K9me3) in mouse embryos derived from nuclear transfer than embryos from in
vitro fertilization (using a sperm and egg).<span style="mso-spacerun: yes;">
</span>These regions were associated with decreased gene expression and compact
DNA.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMs0NEWKBXeQ180OyDtALuvRPX-Yj9adOLOzZ4agfUbMc9k0BDeFt3BzxvFoQ6ooZlClh563ukROIAgd4lUCFJ_sFTWboqxbznN_orJ8PA-5TpNjwrGFuYXMHBF4AJrrQ-KWaPsmzrJlWB/s1600/SCNT+epigenetic+problem.png" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgMs0NEWKBXeQ180OyDtALuvRPX-Yj9adOLOzZ4agfUbMc9k0BDeFt3BzxvFoQ6ooZlClh563ukROIAgd4lUCFJ_sFTWboqxbznN_orJ8PA-5TpNjwrGFuYXMHBF4AJrrQ-KWaPsmzrJlWB/s1600/SCNT+epigenetic+problem.png" height="252" width="640" /></a></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Improving efficiency</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Now we know one of the
problems, but what can researchers do to improve the efficiency of reproductive
cloning?<span style="mso-spacerun: yes;"> </span>Somehow they need to decrease
H3K9me3 modifications in the donor genome.<span style="mso-spacerun: yes;">
</span>They do this two ways:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">(1) There are too many
methylated histones, so the authors injected an enzyme that removes methyl
groups into the one-cell embryos.<span style="mso-spacerun: yes;"> </span>The
embryos expressed more genes and survived throughout development.<span style="mso-spacerun: yes;"> </span>70% of these cloned embryos implanted into a
surrogate mouse uterus and 8% survived to adulthood.<span style="mso-spacerun: yes;"> </span>Those numbers are higher than before, but
still not perfect.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">(2) They also tried
decreasing expression of the enzymes that put on the methyl groups.<span style="mso-spacerun: yes;"> </span>This also improved development, so 50% of the
embryos made it to later stages of development, but they did not see how many
survived to adulthood.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">There is an epigenetic
barrier for nuclear transfer from adult cells in mouse oocytes.<span style="mso-spacerun: yes;"> </span>Presumably a similar problem is preventing
cloning in other organisms as well.<span style="mso-spacerun: yes;"> </span>It
makes sense that an adult cell would have a different pattern of epigenetic
modifications than an embryonic genome.<span style="mso-spacerun: yes;">
</span>The authors were able to improve cloning efficiency by decreasing the
H3K9me3 modification, but there are probably other histone modifications that
are also different in adults.<span style="mso-spacerun: yes;"> </span>There is
still a long way to go before cloning is a reliable procedure, but at least now
we have some explanation of why it is so difficult.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-8280134506209435472014-09-07T11:47:00.000-07:002014-09-07T14:47:35.315-07:00Transgenerational inheritance of fear<span style="font-family: Arial;">A new semester has begun and
I have no extra time to update this blog, so just a short entry today.<span style="mso-spacerun: yes;"> </span>This paper was just too cool to pass up.<span style="mso-spacerun: yes;"> </span>It was published earlier this year in <a href="http://www.nature.com/neuro/journal/v17/n1/full/nn.3594.html" target="_blank">Nature Neuroscience by Dias and Ressler</a>.<span style="mso-spacerun: yes;"> </span>They
conducted a series of experiments which showed that learned fear can be passed
on from generation to generation in the sperm DNA.<span style="mso-spacerun: yes;"> </span>That’s Lamarckian evolution for all you
evolution nerds out there.<span style="mso-spacerun: yes;"> </span>A learned
behavior that is inherited genetically -- totally crazy!</span>
<br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The DNA sequence itself
isn’t changing, but instead the expression of genes is altered, so different
amounts of proteins are being made.<span style="mso-spacerun: yes;"> </span>This
process is known as epigenetics (which <a href="http://www.cellways.blogspot.com/2012/03/take-two-hdac-inhibitors-and-call-me-in.html" target="_blank">I’ve discussed before</a> with regard to
histone modifications).<span style="mso-spacerun: yes;"> </span>One way to
change DNA expression is by methylating cytosines (the “C” in DNA
sequences).<span style="mso-spacerun: yes;"> </span>The methyl group (CH3) makes
it harder for proteins to bind to the DNA and transcribe the genes into mRNA
and subsequently into protein.<span style="mso-spacerun: yes;"> </span>The
general rule of thumb is: more methylation --> less gene expression, less methylation --> more gene expression.<span style="mso-spacerun: yes;"> </span>This is a common way our cells regulate gene
expression, and what’s really interesting is that many external influences can
affect DNA methylation, like traumatic life experiences, smoking, exercise,
environmental toxins, etc. </span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgfSh51MeQCXqLXPuEeITRUA8HJBPQFL4Pb9ZtlXbzG7hT7gWUoeuPvlQe7qGelqy6mbJmCHgG8MeI8kbZfw5gaF5L3SDONMNjzqfNMDiMZgqbadtNgGqYwmOqFAob8HXKzVx2KK7MjkRwu/s1600/Cytosine_5-methylation.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgfSh51MeQCXqLXPuEeITRUA8HJBPQFL4Pb9ZtlXbzG7hT7gWUoeuPvlQe7qGelqy6mbJmCHgG8MeI8kbZfw5gaF5L3SDONMNjzqfNMDiMZgqbadtNgGqYwmOqFAob8HXKzVx2KK7MjkRwu/s1600/Cytosine_5-methylation.png" height="113" width="320" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Cytosine getting methylated (note the H3C addition on the the molecule on the right)</td></tr>
</tbody></table>
<div class="MsoNormal">
<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">It is conceivable that DNA
methylation patterns can be inherited through generations, so changes in gene
expression that affected your great grandparents could still be maintained in
your cells.<span style="mso-spacerun: yes;"> </span>Most of these types of
studies focus on changes that occur to the mom during pregnancy.<span style="mso-spacerun: yes;"> </span>For example, lets say that researchers expose
a pregnant mouse to a toxin that may affect DNA methylation.<span style="mso-spacerun: yes;"> </span>The next generation (the F1 generation) is
also being exposed in utero to the same toxin.<span style="mso-spacerun: yes;">
</span>The eggs or sperm progenitor cells are also developing in the embryo, so
the next next generation (F2) may also be exposed to the toxin.<span style="mso-spacerun: yes;"> </span>Thus, if you see DNA methylation changes in
the F1 and F2 offspring, this isn’t really so surprising since these cells were
all exposed at the same time as the mom (F0 generation).<span style="mso-spacerun: yes;"> </span>In order to really prove that DNA methylation
patterns can be inherited across generations (transgenerationallly), you need
to expose the parents to a stimulus before conception, before the F1 and F2
generation even exist, which is what they did in this paper.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The authors chose to
initiate changes to gene expression by conducting odor conditioning in
mice.<span style="mso-spacerun: yes;"> </span>They paired a particular odor with
a mild foot shock and conditioned F0 males to be afraid of the odor.<span style="mso-spacerun: yes;"> </span>Then these males mated with naïve females
(never exposed to the odor).<span style="mso-spacerun: yes;"> </span>The F1
offspring showed excessive fear to the conditioned odor, even though they had
never encountered it before.<span style="mso-spacerun: yes;"> </span>It was
their fathers who had been shocked, not them.<span style="mso-spacerun: yes;">
</span>The authors found there were more cells in the olfactory region of their
brains that expressed the olfactory receptor for the conditioned odor.<span style="mso-spacerun: yes;"> </span>Furthermore, their dad’s sperm and their own
sperm were less methylated in the gene that encodes for that particular odor
receptor, so the offspring of F1 were also affected.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">F0 dad learns fear for odor --> decreased methylation for receptor gene --> F1 offspring inherit methylation changes --> express more of the receptor --> increased sensitivity to odor --> F1 sperm have same decreased methylation --> sensitivity for odor passed on to F2 generation
<span style="font-family: Arial;"> </span></span><br />
<br />
<span style="font-family: Arial;"><span style="font-family: Arial;">Grandpa (F0) had a bad
experience with an odor and now his grandkids will be more afraid and sensitive
to that odor.<span style="mso-spacerun: yes;"> </span>And it’s all genetic.<span style="mso-spacerun: yes;"> </span>The authors did a series of experiments to
show that it isn’t behaviorally based (grandpa isn’t telling the grandkids
about his horrible experience with this smell).<span style="mso-spacerun: yes;">
</span>For instance, they took the sperm from the F0 mice and took it to a
different mouse facility and did in vitro fertilization, so the father was nowhere
near his offspring or the mother.<span style="mso-spacerun: yes;"> </span>The F1
mice from in vitro fertilization were just as super sensitive to the odor.</span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">This is nuts!</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><a href="http://knowingneurons.com/2014/02/19/the-smell-of-the-good-ol-days/" target="_blank">Here's a good blog post about this paper </a></span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-31820344741601729602014-05-24T18:28:00.000-07:002014-05-24T18:28:45.764-07:00Ctenophores come before<div class="MsoNormal">
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-</style><span style="font-family: Arial;">Three months ago, if I had
seen this article about the ctenophore genome, I would have moved right passed
it without a second look.<span style="mso-spacerun: yes;"> </span>What is a
ctenophore and why would I care about the sequence of its DNA?<span style="mso-spacerun: yes;"> </span>But then I taught Bio 2 this spring and
learned about animal diversity and the evolutionary tree (a day before I taught
it).<span style="mso-spacerun: yes;"> </span>This is a great example that the
more you learn, the more interested you become in the subject.<span style="mso-spacerun: yes;"> </span>Today’s article by Moroz et al. was published
recently online in Nature (this one is open access, so <a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature13400.html" target="_blank">take a look</a>).<span style="mso-spacerun: yes;"> </span>The results totally change the roots of the
animal tree and invalidate what we taught to our students this semester.<span style="mso-spacerun: yes;"> </span>Before we get into the paper, let me answer
my own questions:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">What is a ctenophore?</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Ctenophores are also known
as comb jellies, because they look like jellyfish and have a comb-like
structure that they wiggle around to move through the water.<span style="mso-spacerun: yes;"> </span>They have sensory organs to sense light and
gravity.<span style="mso-spacerun: yes;"> </span>They have tentacles that they
move with their nervous system in order to catch prey.</span></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggZDbOT1iDp6G2XYOstJOa-nArt20EAygELBdYcZKAuMsxwRJ2Vmj6dnFjW4sRllKE3kzJmTl-BOYbaH_KOdBRZB9jVk-gaHiF_aGTYcmL4F6k9V_vr67MyYPIT0XWRIYp3k-rnTL591ym/s1600/LightRefractsOf_comb-rows_of_ctenophore_Mertensia_ovum.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEggZDbOT1iDp6G2XYOstJOa-nArt20EAygELBdYcZKAuMsxwRJ2Vmj6dnFjW4sRllKE3kzJmTl-BOYbaH_KOdBRZB9jVk-gaHiF_aGTYcmL4F6k9V_vr67MyYPIT0XWRIYp3k-rnTL591ym/s1600/LightRefractsOf_comb-rows_of_ctenophore_Mertensia_ovum.jpg" height="320" width="176" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Comb jelly (from Wikimedia Commons)</td></tr>
</tbody></table>
<span style="font-family: Arial;"> </span><span style="font-family: Arial;">Although they look like
jellyfish, they are in a totally different phylum, or branch of the
evolutionary tree (also known as a phylogenetic tree).<span style="mso-spacerun: yes;"> </span>Jellyfish are in the phylum Cnidaria, along
with sea anemones, coral and hydras.<span style="mso-spacerun: yes;">
</span>Comb jellies are in their own phylum known as Ctenophora.<span style="mso-spacerun: yes;"> </span></span>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Why should we care about
ctenophores?</span></b><span style="font-family: Arial;"> </span>
</div>
<div class="MsoNormal">
<span style="font-family: Arial;">Ctenophores, along with
cnidarians and sponges, represent some of the most ancient lineages of
animals.<span style="mso-spacerun: yes;"> </span>Studying them can give us a
clue about how animals evolved.<span style="mso-spacerun: yes;"> </span>All the
rest of the animals are in the large taxonomic group called Bilateria, because
they have bilateral symmetry (which is symmetry across a single axis).<span style="mso-spacerun: yes;"> </span>This includes humans, insects, crustaceans,
worms, fish, molluscs, etc.<span style="mso-spacerun: yes;"> </span>Think about
a jellyfish or a sea anemone; they have radial symmetry, which means they can
be bisected in lots of different axes and you would still have symmetrical
halves.<span style="mso-spacerun: yes;"> </span>The bilateral animals are more
complicated in lots of other ways, such as having a greater variety of tissues
and more complex physiology.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">The phylogenetic tree
according to the biology textbook</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Sponges don’t have organized
tissues and they don’t have a nervous system, so based on that, researchers
have considered them to be the most ancient lineage (i.e. the “basal”
animals).<span style="mso-spacerun: yes;"> </span>So if we are building a
phylogenetic tree based on morphological characteristics, we are going to put
them as the first branch.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Cnidarians and ctenophores
look very similar, so it would make sense to put them right next to each other,
followed by the bilateral animals.<span style="mso-spacerun: yes;"> </span>Thus,
based on morphological observations, the tree should look something like this:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRKBSur8dNLndVLk6ohMA0V2w87BZtWk70WjnLK4TpoKW12mPwhjTqkIGlifYYXcbPH5Hy5G3xK0WIAIdSxMRe67IMzTVTq38yu92i0R2D-BY02WkmrC2te0sTsBm8X3CT0Jf4ZBzPgCYl/s1600/Old+tree.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgRKBSur8dNLndVLk6ohMA0V2w87BZtWk70WjnLK4TpoKW12mPwhjTqkIGlifYYXcbPH5Hy5G3xK0WIAIdSxMRe67IMzTVTq38yu92i0R2D-BY02WkmrC2te0sTsBm8X3CT0Jf4ZBzPgCYl/s1600/Old+tree.jpg" height="226" width="400" /></a></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">No one ever explained to me
why cnidarians get to be closer to the bilaterals than ctenophores.<span style="mso-spacerun: yes;"> </span>Perhaps this is because the cnidarians come
in so many different body plans, so maybe they are considered to be more
complex and thus, an evolutionarily “newer” animal.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">We told our students over
and over: “Sponges are the most basal animals”.<span style="mso-spacerun: yes;">
</span>But like many phylogenetic theories that have come before, new DNA
sequencing data is challenging this view.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">What does the ctenophore
genome tell us?</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">First off, for the
non-biologists out there, you need to understand one fundamental thing about
gene evolution.<span style="mso-spacerun: yes;"> </span>Two species that are
highly related will have very similar DNA sequences.<span style="mso-spacerun: yes;"> </span>The further apart two species are in
evolutionary time, the more time there is for mutations to change the DNA
sequences and the gene functions.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Moroz et al. sequenced one
of the ctenophore genomes and then compared it with the genomes of sponges and
cnidarians.<span style="mso-spacerun: yes;"> </span>One of the main findings was
that there are many missing animal-specific genes that are involved in animal
development (Hox genes), regulating gene expression (no miRNAs!) and innate
immunity.<span style="mso-spacerun: yes;"> </span>Although some animal-specific
genes are absent, the ctenophores have many unique genes that are not found in
other animals, indicating that these genes evolved independently in the
ctenophore lineage.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The researchers devoted a
lot of the paper to looking at genes involved in nervous system function.<span style="mso-spacerun: yes;"> </span>Ctenophores, like cnidarians, have neural
nets, as opposed to organized bundles of nerves.<span style="mso-spacerun: yes;"> </span>Bilateral animals have many different
neurotransmitters, which are the signals that get sent between nerve
cells.<span style="mso-spacerun: yes;"> </span>The ctenophores only have genes
for making the neurotransmitter glutamate (and GABA), but they have a ton of
glutamate receptors, more than other animals.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">All of these findings led
the authors to conclude that ctenophores are the most basal animals, not
sponges.<span style="mso-spacerun: yes;"> </span>Alternatively, it is still
possible to keep the same phylogenetic tree, but there would need to have been massive
gene loss in the ctenophore lineage.<span style="mso-spacerun: yes;"> </span>The
most parsimonious explanation is shown here:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5j7XKwqaYvV2kwY14sUFvlUvhxCETqqO3QuA5aCy-XRxHfkFwGrzDXto5DtWqjCPpD8sJkRZBzydNlrmeBdmKQlPLsv18vIb6hOBQt8kS9h7PoJfQ9MbbEpv-vmCUM-SO1N4BHd-ysMhE/s1600/new+tree.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi5j7XKwqaYvV2kwY14sUFvlUvhxCETqqO3QuA5aCy-XRxHfkFwGrzDXto5DtWqjCPpD8sJkRZBzydNlrmeBdmKQlPLsv18vIb6hOBQt8kS9h7PoJfQ9MbbEpv-vmCUM-SO1N4BHd-ysMhE/s1600/new+tree.jpg" height="265" width="400" /></a></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The main difference between
these two trees is that the sponges and ctenophores have swapped
positions.<span style="mso-spacerun: yes;"> </span>Note that this would require
a nervous system to have developed twice independently.<span style="mso-spacerun: yes;"> </span>That’s totally insane.<span style="mso-spacerun: yes;"> </span>The ctenophores and the cnidarians “needed” a
method of controlling their body to capture prey and both lineages “came up”
with the same solution (of course evolution is random and doesn’t have a
particular goal in mind).<span style="mso-spacerun: yes;"> </span>When similar
structures evolve independently, this is known as convergent evolution.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Next year, instead of
devoting half a lecture to sponges and tossing in a single slide on
ctenophores, I think I’ll have to give ctenophores their due, as potentially
the most ancient lineage of animals still in existence.<span style="mso-spacerun: yes;"> </span></span></div>
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<br /></div>
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<span style="font-family: Arial;">Carl Zimmer always beats me
to the punch, so <a href="http://news.nationalgeographic.com/news/2014/05/140521-comb-jelly-ctenophores-oldest-animal-family-tree-science/" target="_blank">here’s his take</a> on the same article.<span style="mso-spacerun: yes;"> </span>Better writing, but fewer trees!</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-44287013825978986732014-01-15T16:43:00.001-08:002014-01-21T11:25:10.219-08:00The mosaic female brain<span style="font-family: Arial,Helvetica,sans-serif;">Female mammals have two copies of the X chromosome while
males have only one copy (because they have a Y chromosome instead).<span style="mso-spacerun: yes;"> </span>Chromosomes contain genes and <a href="http://www.cellways.blogspot.com/p/fundamentals.html" target="_blank">genes are the instructions for making proteins</a>, so if females have twice as many copies of
each gene on the X chromosome, will they make twice as much protein?<span style="mso-spacerun: yes;"> </span>The answer to that is mostly “no”.<span style="mso-spacerun: yes;"> </span>In young female embryos, one X chromosome is
randomly inactivated and will remain that way through her life.<span style="mso-spacerun: yes;"> </span>The chromosome gets compacted into a
structure known as a Barr body.<span style="mso-spacerun: yes;"> </span>However,
when X inactivation occurs there are many embryonic cells and each one can
inactivate one copy or the other.<span style="mso-spacerun: yes;"> </span>Why
does this matter?<span style="mso-spacerun: yes;"> </span>Well, remember that
one X chromosome came from dad and one from mom, so there may be different
variants for each gene; different versions of proteins can be made depending on
which X chromosome is still active in that cell.<span style="mso-spacerun: yes;"> </span>In other words, <a href="http://www.amazon.com/Females-Are-Mosaics-Inactivation-Differences/dp/0199927537" target="_blank">females are genetic mosaics</a>, where each cell may express one X chromosome or the
other.<span style="mso-spacerun: yes;"> </span>That’s cool!</span><br />
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<span style="font-family: Arial,Helvetica,sans-serif;"><br /></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;">What if the female embryo inherits one good copy of a gene
and one bad copy that is non-functional and disease-causing?<span style="mso-spacerun: yes;"> </span>Some of her cells would express the good copy
of the gene and be fine and other cells would express the bad copy and be
messed up.<span style="mso-spacerun: yes;"> </span>The severity of the disease
for this female will depend on how many cells inactivated the good copy and
where these cells are located in the body.<span style="mso-spacerun: yes;">
</span>Imagine that X inactivation occurred at the 4 cell stage, where two
cells inactivate the good chromosome and the other two cells inactivate the bad
chromosome.<span style="mso-spacerun: yes;"> </span>Once an X chromosome is
inactivated, it will stay that way in all the cells that are formed from that
original cell in the 4 cell stage (see the figure below).<span style="mso-spacerun: yes;"> </span>If each one of those 4 cells divides the same
amount to form the final adult form, then you would expect half of her cells to
be messed up and half of them to be fine.<span style="mso-spacerun: yes;">
</span>But what if the two cells with the active bad chromosome happen to be
cells that will divide way more and make way more future tissues of the
body?<span style="mso-spacerun: yes;"> </span>Then in the adult form, she would
have tons of messed up cells and probably have a much more severe version of
the disease.</span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgbbKaf5ghRXe9K6ibaTIP7tPyMOT20kmY_X9Rwo9REpAIb3edZaaKg4JnQfsBQB8RIZf3plcWJQcS5czc4A5RbF4pwWwfV-pi4oMn6k4CX62KHX-mxWOyucoi-Ihu0Jdd2mTjQGGEXDRF9/s1600/simple+x+inactivation.jpeg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgbbKaf5ghRXe9K6ibaTIP7tPyMOT20kmY_X9Rwo9REpAIb3edZaaKg4JnQfsBQB8RIZf3plcWJQcS5czc4A5RbF4pwWwfV-pi4oMn6k4CX62KHX-mxWOyucoi-Ihu0Jdd2mTjQGGEXDRF9/s1600/simple+x+inactivation.jpeg" height="302" width="400" /></a></span></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;">In females one X chromosome is inactivated early in development (image from www.scoop.it)</span></td></tr>
</tbody></table>
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<span style="font-family: Arial,Helvetica,sans-serif;">As I mentioned earlier, X inactivation actually happens
later on in embryonic development when there are more cells and each one can
choose to inactivate one chromosome or the other.<span style="mso-spacerun: yes;"> </span>If we consider the disease scenario, this
random nature of X inactivation can lead to huge variability in X-linked
disease expression in females.<span style="mso-spacerun: yes;"> </span>It’s also
important to think about how certain types of cells and tissues develop.<span style="mso-spacerun: yes;"> </span>If an entire tissue develops from a single
cell after X inactivation, then all of the cells in that tissue will have the
same inactivated chromosome.<span style="mso-spacerun: yes;"> </span></span>
</div>
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<span style="font-family: Arial,Helvetica,sans-serif;">Researchers at John
Hopkins University
visualized X inactivation by marking expression from each X chromosome with a
different fluorescent protein.<span style="mso-spacerun: yes;"> </span>Wu et al
published their beautiful images in a <a href="http://www.cell.com/neuron/abstract/S0896-6273%2813%2901003-9" target="_blank">recent article in the journal <i>Neuron</i></a>.</span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><b>Marking X chromosomes</b></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;">The authors created two types of mice, which each had an
extra inserted gene on the X chromosome.<span style="mso-spacerun: yes;">
</span>One type had a gene that encodes a red fluorescent protein called
tdTomato.<span style="mso-spacerun: yes;"> </span>The other mice had a gene for
the green fluorescent protein, or GFP, which was originally discovered in
jellyfish.<span style="mso-spacerun: yes;"> </span>They then mated these two
mice together and used the female offspring that had one X with tdTomato (X<sub>t</sub>)
and one X with GFP (X<sub>G</sub>).<span style="mso-spacerun: yes;"> </span>If
the “red” chromosome is inactivated, then only GFP will be expressed and this
cell will look green, as will all of its daughter cells.<span style="mso-spacerun: yes;"> </span>This way they can look at the heterogeneity
of X chromosome expression in different parts of the body.<span style="mso-spacerun: yes;"> </span></span></div>
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<div class="separator" style="clear: both; text-align: center;">
<span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqernV2o-9nPcgOFLR-MxV5xpqX4OULg2qdfizvgesql1iItm9P29J_JjZvJWccSrwO91s_xVuLR96i29ikULA1RbAbS4oY6gsglfsL0_h89e3ZadE5IhmE4VE1-qZ9Jyf3LjX9971UTI0/s1600/Figure+2+-+marking+cells.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgqernV2o-9nPcgOFLR-MxV5xpqX4OULg2qdfizvgesql1iItm9P29J_JjZvJWccSrwO91s_xVuLR96i29ikULA1RbAbS4oY6gsglfsL0_h89e3ZadE5IhmE4VE1-qZ9Jyf3LjX9971UTI0/s1600/Figure+2+-+marking+cells.jpg" height="272" width="640" /></a></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><b>The results</b></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;">Overall, the mice came in all different amounts of red and
green.<span style="mso-spacerun: yes;"> </span>For instance one mouse might be
nearly all green while its sibling is all red, again indicating that X
inactivation is a random process.<span style="mso-spacerun: yes;"> </span>In the
mice that had both red and green, it was interesting to see the different
patterns in the body.<span style="mso-spacerun: yes;"> </span>For instance, in
the intestine, cells of the same color were found in columns.<span style="mso-spacerun: yes;"> </span>That’s because the cells in the column
originate from one single stem cell, so they should all contain the same active
X chromosome.</span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjJSerOmctAsUumLdNRAMoaggco99yPMbWKeR0nEOCINZH-W-MxOixOLuWZEhtQFBbm64ngVrPycv7G9ASnuhA84Hl6SpWDBk073z2R24-80C830xreOAW_xopeQMT5BQw6gJS-cN3wcj3f/s1600/Figure+3+-+intestine.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEjJSerOmctAsUumLdNRAMoaggco99yPMbWKeR0nEOCINZH-W-MxOixOLuWZEhtQFBbm64ngVrPycv7G9ASnuhA84Hl6SpWDBk073z2R24-80C830xreOAW_xopeQMT5BQw6gJS-cN3wcj3f/s1600/Figure+3+-+intestine.jpg" height="245" width="400" /></a></span></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;">X inactivation appears in columns in intestinal tissue, because cells from a single stem cell migrate together</span></td></tr>
</tbody></table>
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<span style="font-family: Arial,Helvetica,sans-serif;"><br /></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"> Another interesting finding was that skeletal muscle cells
expressed both red and green fluorescent proteins.<span style="mso-spacerun: yes;"> </span>This would seem to indicate that there is no
X inactivation in muscle, but this is not the case.<span style="mso-spacerun: yes;"> </span>Skeletal muscles are actually formed by
muscle progenitor cells (myoblasts) that fuse together, creating cells with
multiple nuclei and copies of the genome.<span style="mso-spacerun: yes;">
</span>If a cell with an active “green” X chromosome and a cell with an active “red”
chromosome fuse together, then the muscle will express both proteins.<span style="mso-spacerun: yes;"> </span>This only works for skeletal muscle; cardiac
muscle in the heart does not develop by cell fusion, so these muscle cells are
either red or green.<span style="mso-spacerun: yes;"> </span>This is a great demonstration
of the differences in muscle development.
</span></div>
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<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0NIckk7smX1HiWV4nHBx3JsfzhoE1AQO6ZeH-C2VLVVmHeaUSbssp59Mn3i03MrBJd7mxKaAznOE26ga-Cr0Cnx2DktPXgWhURH4X2whGFHpoae7OD-1-eYDA7VzBJolt61Pzf5urSAYy/s1600/Figure+4+-+skeletal+muscle.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEg0NIckk7smX1HiWV4nHBx3JsfzhoE1AQO6ZeH-C2VLVVmHeaUSbssp59Mn3i03MrBJd7mxKaAznOE26ga-Cr0Cnx2DktPXgWhURH4X2whGFHpoae7OD-1-eYDA7VzBJolt61Pzf5urSAYy/s1600/Figure+4+-+skeletal+muscle.jpg" height="188" width="400" /></a></span></td></tr>
<tr><td class="tr-caption" style="text-align: center;"><span style="font-family: Arial,Helvetica,sans-serif;">Skeletal muscle cells express both X chromosomes, because they are formed via cell fusion</span></td></tr>
</tbody></table>
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<span style="font-family: Arial,Helvetica,sans-serif;"> They also noticed clear differences between the left and
right side of the body, like in the tongue, retinas and brain.<span style="mso-spacerun: yes;"> </span>This indicates that progenitor cells stay
segregated to either the left or right side during development.<span style="mso-spacerun: yes;"> </span>In other words, there is not a lot of
migration between the two sides of the body, where a cell on the right side
would make cells for the left side of the body, and vice versa.
</span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><br /></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><b>The mosaic brain</b></span></div>
<div class="MsoNormal">
<span style="font-family: Arial,Helvetica,sans-serif;">The main focus of this paper is on the heterogeneity in the
nervous system.<span style="mso-spacerun: yes;"> </span>They looked at two
different cell types in the brain: excitatory pyramidal cells and inhibitory
interneurons.<span style="mso-spacerun: yes;"> </span>These two types of neurons
develop from different areas of the embryonic brain.<span style="mso-spacerun: yes;"> </span>They found that inhibitory interneurons were
highly mixed.<span style="mso-spacerun: yes;"> </span>When they quantified the
fraction of red inhibitory cells in two different parts of the brain, the
values were very similar.<span style="mso-spacerun: yes;"> </span>On the other
hand, when looking at excitatory neurons, there was a lot of variability of
which X chromosome was inactivated, across different parts of the brain and in
different animals.<span style="mso-spacerun: yes;"> </span>If there was an
X-linked gene that affected excitatory neuron function, then the effects on
neuronal circuits would be different for different regions of the brain in an
individual.<span style="mso-spacerun: yes;"> </span>The authors suggest that
this could actually be a good thing, because it would allow females with
different genetic variants to respond to a range of stimuli, increasing the
dynamic range.<span style="mso-spacerun: yes;"> </span></span></div>
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<span style="font-family: Arial,Helvetica,sans-serif;"><br /></span></div>
<span style="font-family: Arial,Helvetica,sans-serif;"><span style="font-size: 12.0pt; mso-ansi-language: EN-US; mso-bidi-language: AR-SA; mso-fareast-font-family: "MS Mincho"; mso-fareast-language: JA;">So there are bad aspects of X chromosome inactivation, like the
expression of X-linked diseases, but there are also some good points, like
increased functional diversity of neurons.<span style="mso-spacerun: yes;">
</span>The authors suggest that X inactivation “may represent one of the more
significant mechanisms by which individual differences in central nervous system
function are generated.”<span style="mso-spacerun: yes;"> </span>It is crazy to
think that random inactivation of a chromosome in the early embryo might give
us our future individual personalities.<span style="mso-spacerun: yes;"> </span></span></span>Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-70365411729426391802013-12-27T12:13:00.001-08:002014-01-24T20:43:10.457-08:00Release the sperm!<span style="font-family: Arial;">While preparing a class
about synthetic biology, I came across this older paper that actually shows a
practical application for synthetic biology.<span style="mso-spacerun: yes;">
</span><a href="http://www.sciencedirect.com/science/article/pii/S016836591000920X" target="_blank">Kemmer et al. describe</a> a new technique for artificial insemination of
cows in the Journal of Controlled Release (in 2011).<span style="mso-spacerun: yes;">
</span>I’m not condoning these practices in cows; that is a debate for another
day.<span style="mso-spacerun: yes;"> </span>I am much more interested in the
biology behind this ingenious way of improving the timing of artificial
insemination.<span style="mso-spacerun: yes;"> </span>Let’s get into it.</span><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Luteinizing hormone</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Before I describe the
synthetic circuits, we have to go over what the luteinizing hormone (LH)
does.<span style="mso-spacerun: yes;"> </span>LH is released from the pituitary
gland in the brain and travels through the blood to the gonads (in males and
females).<span style="mso-spacerun: yes;"> </span>In females, there is a huge
surge of LH release once a month, which triggers the release of an oocyte (an
egg) from the mature follicle in the ovaries.<span style="mso-spacerun: yes;">
</span>In other words, increased LH causes ovulation.<span style="mso-spacerun: yes;"> </span>The LH hormone binds to LH receptors (LHR)
which are expressed on the surface of the target cells in the ovary.<span style="mso-spacerun: yes;"> </span>When LH binds its receptors, it triggers a
molecular cascade inside the target cell, which leads to the production of
another molecule called cyclic AMP (cAMP).<span style="mso-spacerun: yes;">
</span>cAMP is a versatile molecule that can initiate lots of cellular
responses, like changes in gene expression or activation of enzymes.</span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The current practice in cow
farming is to keep an eye on the female cows and when they appear to be in
estrus, then the farmers inject sperm into the cow and hope for the best.<span style="mso-spacerun: yes;"> </span>Different cows, though, will have different
durations of estrus, so it is sort of a guessing game to time the insemination
perfectly.<span style="mso-spacerun: yes;"> </span>The LH surge regulates
release of the oocytes, so what if you could design a synthetic system that
also releases sperm in response to LH?<span style="mso-spacerun: yes;">
</span>The sperm will be encapsulated and inert until the LH surge initiates
the release of the sperm from their holding cell.<span style="mso-spacerun: yes;"> </span>The farmer could inseminate the female cow
when estrus appears to be close at hand and the female’s own LH will release
the sperm at just the right time when the oocyte is naturally released.<span style="mso-spacerun: yes;"> </span></span></div>
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<br /></div>
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<span style="font-family: Arial;">How can the researchers
design a holding cell for sperm that is responsive to LH?</span></div>
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<br /></div>
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<b><span style="font-family: Arial;">The synthetic circuit</span></b></div>
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<span style="font-family: Arial;">The holding cell is going to
be a little hollow bead of cellulose (diameter = 350-400 </span><span style="font-family: Symbol;">u</span><span style="font-family: Arial;">m).<span style="mso-spacerun: yes;"> </span>Cellulose
is a naturally occurring molecule made up of lots of glucose sugars hooked
together.<span style="mso-spacerun: yes;"> </span>The cellul<u>o</u>se beads
will stay intact unless there is an enzyme called cellul<u>a</u>se to break all
those bonds between the sugars.<span style="mso-spacerun: yes;"> </span>The
researchers envelop living sperm and modified mammalian cells inside the microbeads
and these get injected into the uterus of the female cow.<span style="mso-spacerun: yes;"> </span>The sperm seem to be happy inside the
cellulose and are still functional when they are later released.</span></div>
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<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimnAIYufBwxsmNZz3fE0zKj9jM5qblI3aZX7bliR2kP3j-MQ99yrKxd2OObaISEhm4i6N_mu9uz2hlDRalo3uZiab_bJPgvxd4vXQy2TIroRec2abU9wsPUM0aJqnz2oVYQHI9_wsGhL4j/s1600/131227+cellulose+beads.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEimnAIYufBwxsmNZz3fE0zKj9jM5qblI3aZX7bliR2kP3j-MQ99yrKxd2OObaISEhm4i6N_mu9uz2hlDRalo3uZiab_bJPgvxd4vXQy2TIroRec2abU9wsPUM0aJqnz2oVYQHI9_wsGhL4j/s320/131227+cellulose+beads.jpg" height="292" width="320" /></a></div>
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<span style="font-family: Arial;"></span><span style="font-family: Arial;"> </span>
</div>
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<span style="font-family: Arial;">The modified cells have two
engineered transgenes:</span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">1) We want these cells to be
responsive to LH, so the cells must express the LH receptor.<span style="mso-spacerun: yes;"> </span>The researchers find that the rat LHR
actually works best, so these cells will have the gene for making the rat LHR.</span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">2) Remember that when LH
binds to LHR, there will be a rise of cAMP inside the cell.<span style="mso-spacerun: yes;"> </span>cAMP will activate a protein called CREB that
binds to DNA and activates expression of genes (I’m skipping a few steps
here).<span style="mso-spacerun: yes;"> </span>Okay, so LH will bind LHR, cAMP
levels will increase, CREB will be activated and will bind to specific DNA
sequences in front of genes.<span style="mso-spacerun: yes;"> </span>The
researchers put the cellulase gene right after a CREB binding sequence in the
second transgene.<span style="mso-spacerun: yes;"> </span>CREB should bind to
the DNA and activate expression of the cellulase gene.</span></div>
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<br /></div>
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<span style="font-family: Arial;">Hopefully you can see where
this going now.<span style="mso-spacerun: yes;"> </span>When LH is released
during ovulation, it will also bind to these modified cells and cause
expression of cellulase (the enzyme that breaks down cellulose).<span style="mso-spacerun: yes;"> </span>The cellulose surrounding the sperm will be
destroyed and the sperm will be released at the same time as the egg.<span style="mso-spacerun: yes;"> </span>Bam!</span></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj3vJje-jVwV0wa6ydo2IaZpRpOPRCnWGkdA8H9eqeX7ZvTe39UGIfDW0jFXAHEV-jM-s7KXmi6EC_oIIyAnFVQljr_0ag8FwSLbzjw61vJ5kvUERLGe4H_Qi-Z9vosrkx8i8_bWPHgiI9k/s1600/131227+cartoon.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEj3vJje-jVwV0wa6ydo2IaZpRpOPRCnWGkdA8H9eqeX7ZvTe39UGIfDW0jFXAHEV-jM-s7KXmi6EC_oIIyAnFVQljr_0ag8FwSLbzjw61vJ5kvUERLGe4H_Qi-Z9vosrkx8i8_bWPHgiI9k/s400/131227+cartoon.jpg" height="342" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">The two pathways initiated by the LH surge. On the left is one of the modified cells inside the cellulose capsule.</td></tr>
</tbody></table>
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<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Does it work?<span style="mso-spacerun: yes;"> </span>The researchers inserted the cellulose
implants into the uterus of Swiss dairy cows.<span style="mso-spacerun: yes;">
</span>Next they injected the cows with a hormone that triggers release of LH.<span style="mso-spacerun: yes;"> </span>The capsules were degraded and sperm released
at the same time as the cow naturally released an oocyte.<span style="mso-spacerun: yes;"> </span>Fertilization occurred and embryos developed
via this well-timed artificial insemination.<span style="mso-spacerun: yes;">
</span>The sperm capsules significantly increase the time window for artificial
insemination, which takes the guess work out of insemination.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Look, synthetic biology
working in a useful setting, rather than in bacteria or mice. </span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-7324444834172094312013-12-23T20:37:00.000-08:002013-12-23T20:37:24.717-08:00Probiotics for autism
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<span style="font-family: Arial;">The human microbiome is a
hot topic in biology these days.<span style="mso-spacerun: yes;"> </span>It is
becoming clear that the microbes living in and on our body can have major
consequences for our health and happiness.<span style="mso-spacerun: yes;">
</span>In fact, abnormalities in the gut microbiome may underlie one of the
great medical mysteries of our time: autism.<span style="mso-spacerun: yes;">
</span>That some bacteria in our intestines could affect our behaviors and
brain development is mind blowing.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Hsiao et al. recently
<a href="http://www.cell.com/abstract/S0092-8674%2813%2901473-6#Summary" target="_blank">published a study in the journal <i style="mso-bidi-font-style: normal;">Cell</i></a>
that investigated the connection between the gut microbiome and autism using a
mouse model of autism.<span style="mso-spacerun: yes;"> </span>They were drawn
to this subject based on the fact that individuals with autism spectrum
disorder (ASD) often have gastrointestinal abnormalities, like irritable bowel
syndrome and increased intestine permeability.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;">Autistic mice?</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Apparently you can produce
mice that exhibit the “core communicative, social and stereotyped impairments”
associated with ASD, by injecting their pregnant mothers with a molecule that stimulates
an immune response.<span style="mso-spacerun: yes;"> </span>In humans, maternal
infection is linked to increased risk of autism in their children.<span style="mso-spacerun: yes;"> </span>The production of these mice was the most
questionable part of the paper in my opinion.<span style="mso-spacerun: yes;">
</span>They never call these mice autistic, and the mice do show impairments
associated with neurological diseases.<span style="mso-spacerun: yes;">
</span>So perhaps we should think of it as a model of a generic neurological
disorder.<span style="mso-spacerun: yes;"> </span>For the sake of simplicity,
though, I will refer to them as “autistic mice”, but remember that it is not a
perfect model system.</span></div>
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<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">They find that the autistic
mice have various defects in their gastrointestinal (GI) tract.<span style="mso-spacerun: yes;"> </span>For instance, their intestinal walls are leaky,
so molecules that are not supposed to be absorbed can cross from the gut into
the blood stream.<span style="mso-spacerun: yes;"> </span>This problem seems to
be caused by the fact that these mice express less of the proteins that make
the tight junctions between cells.<span style="mso-spacerun: yes;"> </span>Think
of these as fences between cells, so molecules can’t sneak through there into
the body.<span style="mso-spacerun: yes;"> </span>In an ideal situation, all
molecules that are absorbed from the gut must go through the cells, a process
which is highly regulated.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBan4HQkJLI2_dvEoLcm0w3r9ernwr0bfk1XTLkhmlvkQW0o523aVtA-zxEOGycxClVXNQ7OcopHROy-h6XySuA5Yzvi-HOeOROA1F-K35yoqbuCV5V79OO58iTGy2WcF1SD_RQ_dZrcCI/s1600/TightJunctionfixed+new.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="305" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiBan4HQkJLI2_dvEoLcm0w3r9ernwr0bfk1XTLkhmlvkQW0o523aVtA-zxEOGycxClVXNQ7OcopHROy-h6XySuA5Yzvi-HOeOROA1F-K35yoqbuCV5V79OO58iTGy2WcF1SD_RQ_dZrcCI/s640/TightJunctionfixed+new.jpg" width="640" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Tight junctions prevent molecules from passing from the gut into the blood. Image adapted from dbriers.com</td></tr>
</tbody></table>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">They find a number of
metabolites that are produced in the intestine from bacteria, which end up in
the blood of autistic mice, but not in the normal mice.<span style="mso-spacerun: yes;"> </span>In other words, these are potentially toxic
molecules that they need to get rid of, but the toxins are leaking into the blood of
the autistic mice.<span style="mso-spacerun: yes;"> </span>That’s not good.<span style="mso-spacerun: yes;"> </span>In fact, if you inject one of these molecules
into a normal mouse, it will become more anxious, similar to the autistic
mice.<span style="mso-spacerun: yes;"> </span>They couldn’t reproduce all of the
behaviors of the autistic mice just with this one molecule, but it’s a good
proof of principle.<span style="mso-spacerun: yes;"> </span>Presumably it’s the
build up of all of these metabolites in the blood that cause impairments of the
nervous system.</span></div>
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<br /></div>
<div class="MsoNormal">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;">Dysbiosis of the intestinal flora</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">I love that word
“dysbiosis”.<span style="mso-spacerun: yes;"> </span>It means that the
intestinal microbiome is out of whack.<span style="mso-spacerun: yes;">
</span>The wrong types of bacteria are in there messing stuff up.<span style="mso-spacerun: yes;"> </span>Hsiao et al. found a number of species
present in the autistic mice that were not in normal mice and vice versa.<span style="mso-spacerun: yes;"> </span>Presumably this imbalance in the microbiome
is what is making the gut leaky.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">To prove this, the authors
fed the autistic mice a probiotic (a “good” type of bacteria) called <i style="mso-bidi-font-style: normal;">Bacteroides fragilis</i> (<i>B. frag</i>).<span style="mso-spacerun: yes;"> </span>Interestingly, <i>B. frag</i> never actually
colonized the guts of the mice, but just having it pass through helped to
restore the normal microbiome.<span style="mso-spacerun: yes;"> </span>Some of
the species that were only present in autistic mice disappeared after they
consumed <i>B. frag</i>.<span style="mso-spacerun: yes;"> </span>The leakiness of the
gut was almost completely reversed, including expression of tight junction
proteins.<span style="mso-spacerun: yes;"> </span>It wasn’t a perfect reversal,
but a number of those metabolites in the blood decreased back to normal.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;">Behavior affected by microbiome</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">To review: when a pregnant
mouse has an infection, her offspring show signs of autism (a mouse-version).<span style="mso-spacerun: yes;"> </span>Somehow this infection causes the wrong
bacteria to colonize the guts of the offspring.<span style="mso-spacerun: yes;">
</span>The dysbiosis leads to changes in gene expression and a leaky gut that
allows toxic molecules into the blood stream, thus affecting the development of
the nervous system.<span style="mso-spacerun: yes;"> </span>Consumption of a
probiotic at weaning age fixes a lot of the gut issues.<span style="mso-spacerun: yes;"> </span>Does it also reverse some of the behavior
impairments associated with autism?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The short answer is
yes!<span style="mso-spacerun: yes;"> </span>Autistic mice fed <i>B. frag</i> were less
anxious, less obsessive, more communicative and interacted more
with other mice.<span style="mso-spacerun: yes;"> </span>The test for obsessive
behavior was kind of cute.<span style="mso-spacerun: yes;"> </span>The mice were
put in a cage filled with sand with marbles sitting on top.<span style="mso-spacerun: yes;"> </span>The autistic-like mice bury a greater
percentage of the marbles, demonstrating a stereotyped behavior.</span></div>
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<br /></div>
<div class="MsoNormal">
<b style="mso-bidi-font-weight: normal;"><span style="font-family: Arial;">Yogurt from everyone!</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">If I had an autistic child
and read this paper, I would start them on probiotics right away.<span style="mso-spacerun: yes;"> </span>I mean probiotics are good for everyone,
right, so it definitely seems worth trying.<span style="mso-spacerun: yes;">
</span>In fact, the authors say that <i>B. fragilis</i> is depleted in human ASD
children compared to matched controls.<span style="mso-spacerun: yes;">
</span>Furthermore, probiotics have already been shown to be beneficial in treating
chronic fatigue syndrome.<span style="mso-spacerun: yes;"> </span><span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The authors end their paper
with this bold statement: “We propose the transformative concept that autism,
and likely other behavioral conditions, are potentially diseases involving the
gut that ultimately impact the immune, metabolic, and nervous systems, and that
microbiome-mediated therapies may be a safe and effective treatment for these
neurodevelopmental disorders.”</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-22568997783153785972013-07-11T13:54:00.001-07:002013-07-11T13:56:14.923-07:00Throw another adipocyte on the fire<span style="font-family: Arial;">Humans are able to live in
so many different climates, in a wide range of temperatures and yet our inner
core body temperature remains nearly constant.<span style="mso-spacerun: yes;">
</span>This ability to thermoregulate has something to do, of course, with
clothing and the ability to cool and heat our living spaces, but our bodies
also offer many adaptations to regulate body temperature.<span style="mso-spacerun: yes;"> </span>If it’s too hot, we sweat, releasing excess
heat through evaporative cooling.<span style="mso-spacerun: yes;"> </span>If
it’s too cold, we shiver, producing heat in our working muscles.<span style="mso-spacerun: yes;"> </span>The production of heat through physiological
mechanisms is called thermogenesis and also includes a non-shivering version.<span style="mso-spacerun: yes;"> </span>Today’s paper is about non-shivering
thermogenesis, which is when our fat cells produce heat.</span><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Non-shivering thermogenesis</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">To understand how
non-shivering thermogenesis works, we need to take a step back and discuss
<a href="http://www.cellways.blogspot.com/2012/12/burning-carbs-in-andes.html" target="_blank">cellular respiration</a>.<span style="mso-spacerun: yes;"> </span>The cells of our
body store energy from food in the chemical bonds of a molecule called
ATP.<span style="mso-spacerun: yes;"> </span>During cellular respiration, a cell
will convert glucose or fat into carbon dioxide, while slowly tapping into the
energy in those food molecules in order to make ATP.<span style="mso-spacerun: yes;"> </span>The final step of cellular respiration is
that the energy from the electrons in glucose are passed from protein to
protein, releasing energy that is used to pump protons into a membrane-bound
cellular space.<span style="mso-spacerun: yes;"> </span>You can think of these
protons as a form of potential energy, like stuffing a closet full of
balls.<span style="mso-spacerun: yes;"> </span>When you open up the closet door,
all the balls come tumbling out, releasing their potential energy in the
process.<span style="mso-spacerun: yes;"> </span>During cellular respiration,
this potential energy is used by an enzyme to make ATP.<span style="mso-spacerun: yes;"> </span>During non-shivering thermogenesis, though,
the potential energy stored in all those protons stuffed into a small space is
released by the cell as heat.<span style="mso-spacerun: yes;"> </span>Thus, the
energy from food is used to heat the body rather than being stored in ATP.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The main type of cell that
does non-shivering thermogenesis is brown adipocytes, or fat cells.<span style="mso-spacerun: yes;"> </span>Brown fat is very common in infants, but is
also found in adult humans in the upper chest and neck.<span style="mso-spacerun: yes;"> </span>The purpose of brown fat is to provide heat
for the body.<span style="mso-spacerun: yes;"> </span>Thus, non-shivering
thermogenesis is activated by a drop in body temperature.<span style="mso-spacerun: yes;"> </span>The cold temperature is sensed by the brain, which
activates the sympathetic nervous system (the “fight or flight” response),
which signals to the brown fat cells to express the genes necessary to bypass
ATP production and release heat instead.<span style="mso-spacerun: yes;">
</span><a href="http://www.pnas.org/content/early/2013/06/26/1310261110/suppl/DCSupplemental" target="_blank">In a recent paper published in <i style="mso-bidi-font-style: normal;">PNAS</i></a>,
Ye et al. describe how a different type of fat cell is able to skip all the
nervous system steps and sense the cold directly (red arrow in diagram).<span style="mso-spacerun: yes;"> </span>It is pretty cool that the fat cells are able
to sense temperature, as if they were neurons, and can act autonomously to remedy
the situation.<span style="mso-spacerun: yes;"> </span>No need for a brain here!</span></div>
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<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiPfyjoZ5_tiOJ_inmBLwJOsRXDBeuwTMjnVnSF3VDz9njwf6pXIkFEBKYlCR6goqw4RZtnTwvCWxL1djSTIvn1BRNvIOhZifQ914aCHIWeHQv9fjNF6I1o1FnoKZ8eaOZya5no2iuk_KXG/s1600/non+shivering+thermogenesis+path.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="129" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiPfyjoZ5_tiOJ_inmBLwJOsRXDBeuwTMjnVnSF3VDz9njwf6pXIkFEBKYlCR6goqw4RZtnTwvCWxL1djSTIvn1BRNvIOhZifQ914aCHIWeHQv9fjNF6I1o1FnoKZ8eaOZya5no2iuk_KXG/s640/non+shivering+thermogenesis+path.jpg" width="640" /></a></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Independent thermogenesis</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Through a series of
experiments, the authors demonstrate that a particular type of fat cell will
express genes necessary for non-shivering thermogenesis when exposed to cold,
independent of sympathetic nervous system activation.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">In one experiment, they grew
fat cells at different temperatures and measured gene expression using a
technique called quantitative PCR (qPCR).<span style="mso-spacerun: yes;">
</span>The idea behind this technique is that if a gene is highly expressed,
there will be a lot of mRNA in the cell (<a href="http://www.cellways.blogspot.com/p/fundamentals.html" target="_blank">remember</a> the “central dogma” of molecular
biology) and qPCR is a method for measuring the concentration of mRNA for a
particular gene.<span style="mso-spacerun: yes;"> </span>They focused their
measurements on thermogenic genes that are known to be part of the
non-shivering thermogenesis mechanism, such as Ucp1, which is the enzyme that
actually allows the protons to fall back across the membrane, thereby releasing
their energy as heat.<span style="mso-spacerun: yes;"> </span>They found that
these fat cells that were exposed to the cold expressed more Ucp1 mRNA, even in
the absence of any nervous system.<span style="mso-spacerun: yes;"> </span>These
are just cells in a dish, so this must be an intrinsic property of fat cells.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">It wasn’t just any fat cell
that had this response.<span style="mso-spacerun: yes;"> </span>In fact, brown
adipocytes did not express more Ucp1 in the cold.<span style="mso-spacerun: yes;"> </span>It was a different type of fat cell called a
white adipocyte.<span style="mso-spacerun: yes;"> </span>What is white fat?<span style="mso-spacerun: yes;"> </span>The majority of fat in our body is white fat
and its purpose is to store fat for energy (for cellular respiration) and to
act as a thermal insulator, so we don’t lose as much heat through our skin.<span style="mso-spacerun: yes;"> </span>There is one subtype of white fat that has
been shown to do non-shivering thermogenesis and it was this type that could
express thermogenic genes, like Ucp1, in the cold, independent of the nervous
system.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Okay, so these white fat
cells don’t need input from the nervous system, but do they still use the same
intracellular pathway to turn on expression of these genes?<span style="mso-spacerun: yes;"> </span>Normally, when a fat cell is activated by the
sympathetic nervous system, it sets off a molecular cascade of events inside
the cell, which involves activation of molecules in a pathway called the cAMP
pathway (as shown in the diagram).<span style="mso-spacerun: yes;"> </span>The
authors inhibited this pathway in various ways and found that the cells could
still respond to the cold as before, so this effect must use a different
pathway.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">There are still a number of
open questions, such as: how do fat cells sense temperature?<span style="mso-spacerun: yes;"> </span>Do they use the same types of receptors as
temperature-sensitive neurons?<span style="mso-spacerun: yes;"> </span>Why are
some white fat cells independent, but brown fat cells need the nervous system
to activate thermogenesis?<span style="mso-spacerun: yes;"> </span>One thing
that is clear, however, is that white fat cells are clearly important for
temperature regulation as well as fat storage.<span style="mso-spacerun: yes;">
</span>The authors suggest that tapping into thermogenesis might be a good way
to help obese patients get rid of excess energy storage by releasing it as
heat.<span style="mso-spacerun: yes;"> </span>This pathway that is independent
of the sympathetic nervous system could allow medications to target only the
fat cells without involving the sympathetic nervous system which controls so
many other functions in the body.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Something to think about as
the cold Bay Area summer sets in.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-16890507904147550712013-06-21T18:49:00.000-07:002013-06-21T18:49:45.755-07:00(Insert mildly provocative title here)<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">Ever
seen a pair of pigeons going at it?<span style="mso-spacerun: yes;"> </span>And
did you notice a penis on the male pigeon?<span style="mso-spacerun: yes;">
</span>The answer is no, because most birds do not have external genitalia
large enough for penetration.<span style="mso-spacerun: yes;"> </span>And yet
birds reproduce via internal fertilization.<span style="mso-spacerun: yes;">
</span>Why would evolution favor male genitalia too small to actually enter
into the female?<span style="mso-spacerun: yes;"> </span>This just seems so
inefficient.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">There
are a few birds that do have well developed phalluses, such as the duck and
goose.<span style="mso-spacerun: yes;"> </span>What happened during evolution
that caused some birds to retain a phallus, whereas most other birds lost
it?<span style="mso-spacerun: yes;"> </span>A paper appeared this week in
<a href="http://www.cell.com/current-biology/retrieve/pii/S0960982213005034" target="_blank">Current Biology by Herrera et al.</a>, which addresses these questions from a
developmental point of view.</span><br />
</div>
<b>
</b><br />
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: Arial;">Developmental
arrest</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">The
authors started this study by comparing the development of the phallus in
embryos of two different birds.<span style="mso-spacerun: yes;"> </span>They
chose to look at (1) chick embryos, which are part of the galliformes group of
birds and have reduced phalluses and (2) duck embryos, which are part of the
anseriforms group, which have well developed, penetrating penises.<span style="mso-spacerun: yes;"> </span>They followed the growth of the genital
tubercle, the tissue that will form the penis.<span style="mso-spacerun: yes;">
</span>As the duck and chick embryos grow, so do their genital tubercles, with
no noticeable difference between the two species during the early stages of
development.<span style="mso-spacerun: yes;"> </span>At a later time period,
though, the tubercle stops growing and regresses in the chicks, while the duck
keeps on growing.<span style="mso-spacerun: yes;"> </span>This shows that the
tissue that makes the two different types of phalluses has the same
developmental origin.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: Arial;">Why
does the genital tubercle stop growing in the chick?</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">From
a molecular stand point, the chick embryos could either lose the “growth”
signal or they could gain expression of a “stop” signal not present in ducks.<span style="mso-spacerun: yes;"> </span>From work in other animals, the authors knew
that there are two major growth signals responsible for guiding the development
of the external genitalia – Sonic Hedgehog (Shh) [<a href="http://cellways.blogspot.com/2013/05/go-go-gadget-extendo-filopodia.html" target="_blank">see my other post about this protein</a>] and Hox13.<span style="mso-spacerun: yes;"> </span>These two genes are
strongly expressed in the duck genital tubercle throughout embryonic
development, as expected.<span style="mso-spacerun: yes;"> </span>Surprisingly,
though, they are also strongly expressed in the chick embryos.<span style="mso-spacerun: yes;"> </span>This means that the chickens haven’t lost the
growth signal.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">The
authors then investigated if there is some sort of a “stop” signal in the
chicks.<span style="mso-spacerun: yes;"> </span>They found that in chicks and
quails, with reduced phalluses, there is a lot of cell death in the genital
tubercle in the later stages of development.<span style="mso-spacerun: yes;">
</span>This could account for the regression of the genital tubercle.<span style="mso-spacerun: yes;"> </span>They then found that the chicks highly
express a protein called BMP4 at the tip of the tubercle, which induces cell
death, whereas ducks do not.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">In
fact, by overexpressing BMPs in the duck, they induced cell death in the genital
tubercle.<span style="mso-spacerun: yes;"> </span>In the opposite experiment, they
inhibited BMPs in the chick and their genital tubercles increased growth, as if
they were ducks.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">In
summary:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;"><span style="mso-tab-count: 1;"> </span>Chicken: + BMP </span><span style="font-family: Wingdings; mso-ascii-font-family: Arial; mso-bidi-font-family: Arial; mso-char-type: symbol; mso-hansi-font-family: Arial; mso-symbol-font-family: Wingdings;"><span style="mso-char-type: symbol; mso-symbol-font-family: Wingdings;">--></span></span><span style="font-family: Arial; mso-bidi-font-family: Arial;"> increased cell death </span><span style="font-family: Wingdings; mso-ascii-font-family: Arial; mso-bidi-font-family: Arial; mso-char-type: symbol; mso-hansi-font-family: Arial; mso-symbol-font-family: Wingdings;"><span style="mso-char-type: symbol; mso-symbol-font-family: Wingdings;">--></span></span><span style="font-family: Arial; mso-bidi-font-family: Arial;"> reduced phallus</span></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;"><span style="mso-tab-count: 1;"> </span>Duck:<span style="mso-spacerun: yes;"> </span>- BMP </span><span style="font-family: Wingdings; mso-ascii-font-family: Arial; mso-bidi-font-family: Arial; mso-char-type: symbol; mso-hansi-font-family: Arial; mso-symbol-font-family: Wingdings;"><span style="mso-char-type: symbol; mso-symbol-font-family: Wingdings;">--></span></span><span style="font-family: Arial; mso-bidi-font-family: Arial;"> no cell death, so
continued tissue development </span><span style="font-family: Wingdings; mso-ascii-font-family: Arial; mso-bidi-font-family: Arial; mso-char-type: symbol; mso-hansi-font-family: Arial; mso-symbol-font-family: Wingdings;"><span style="mso-char-type: symbol; mso-symbol-font-family: Wingdings;">--></span></span><span style="font-family: Arial; mso-bidi-font-family: Arial;"> large phallus</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: Arial;">Evolution
of reduced phallus</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">So
what does this mean?<span style="mso-spacerun: yes;"> </span>Chicks and quails
have reduced phalluses, because during development, they express BMP4, which
tells the developing cells of the penis to die off.<span style="mso-spacerun: yes;"> </span>One really cool thing that the authors did
next was to look at cell death in the closest relative to birds-- the
alligator.<span style="mso-spacerun: yes;"> </span>Yah, they got alligator
embryos for this research!<span style="mso-spacerun: yes;"> </span>Alligators
have developed phalluses and they show hardly any cell death in the genital
tubercle.<span style="mso-spacerun: yes;"> </span>From this work, they could
create an evolutionary tree, which shows that chicks and quails most likely evolved
the BMP4 signal after their group separated from ducks.<span style="mso-spacerun: yes;"> </span>Although the authors didn’t test any members
(ha ha) from the neoaves group, which includes most other birds, we can presume
that they also have a similar cell death mechanism to reduce the development of
their phalluses.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCfPv0FOGyaHN5KDQZ96AEFbIi-luGcYlIwNIUlxC0wCknXTb7rBdnfzXCk7hLy8LexRLoPoLUT7m_01d4jU8AYcgbKUELKf_umCLk8yP9QGj5IZ0VrMS57yphEsJgPUnDopqHohOveqF1/s1600/phylogeny.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="305" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgCfPv0FOGyaHN5KDQZ96AEFbIi-luGcYlIwNIUlxC0wCknXTb7rBdnfzXCk7hLy8LexRLoPoLUT7m_01d4jU8AYcgbKUELKf_umCLk8yP9QGj5IZ0VrMS57yphEsJgPUnDopqHohOveqF1/s400/phylogeny.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">Phylogenetic tree of birds, showing when the BMP signal evolved. (Adapted from Herrera et al., 2013)</td></tr>
</tbody></table>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">This
still begs the question of why would natural selection favor a reduced phallus
so much so that it evolved independently in different lineages?<span style="mso-spacerun: yes;"> </span>The authors propose two different theories,
both of which may have occurred:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">1)
Sexual selection – sure, it may not be favorable for the males to have reduced
phalluses, but it might be advantageous for the females.<span style="mso-spacerun: yes;"> </span>In order for insemination to occur in these
species, the female has to be a willing participant to allow the male to shimmy
up next to her and release the sperm in very close proximity.<span style="mso-spacerun: yes;"> </span>This gives the females the power to select
their mates.<span style="mso-spacerun: yes;"> </span>As opposed to species with
large penises, where the male could basically rape the female and still
successfully pass on his genes to the next generation.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">2)
Pleiotropy – this term refers to when a single gene mutation can lead to
multiple noticeable changes in the body.<span style="mso-spacerun: yes;">
</span>BMPs are a major signal during development of animals.<span style="mso-spacerun: yes;"> </span>BMPs are involved in a number of bird-only
innovations such as feathers and beaks.<span style="mso-spacerun: yes;">
</span>Maybe increased BMP expression gave an advantage to these birds, but
also lead to reduced phalluses, as a secondary effect.<span style="mso-spacerun: yes;"> </span>This may have occurred first in evolution,
but sexual selection may have stabilized this characteristic in the population.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: Arial;">This
article was so clear and interesting.<span style="mso-spacerun: yes;">
</span>I’m sure it will catch people’s attention because of the subject matter,
but it’s a great example of using development to solve an evolutionary
question.<span style="mso-spacerun: yes;"> </span>Plus it gives reviewers and
bloggers a great opportunity to think up clever titles and puns for their
articles.<span style="mso-spacerun: yes;"> </span>The review that was published
alongside this article was titled “Cock-a-doodle-don’t”.<span style="mso-spacerun: yes;"> How can I compete with that?</span></span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-1743050481388912162013-05-28T22:07:00.002-07:002013-05-28T22:07:37.097-07:00Stop seizures with a brain graft
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<div class="MsoNormal">
<span style="font-family: Arial;">There are two types of
neurons in the brain: excitatory and inhibitory neurons.<span style="mso-spacerun: yes;"> </span>They do exactly what you think they
would.<span style="mso-spacerun: yes;"> </span>Excitatory neurons release
chemical messengers, which activate other neurons, which may eventually lead to
some sort of perception or action.<span style="mso-spacerun: yes;">
</span>Inhibitory neurons release chemicals that silence other neurons.<span style="mso-spacerun: yes;"> </span>Why would you want inhibitory neurons in your
brain?<span style="mso-spacerun: yes;"> </span>Well, if all your neurons were
excitatory and interconnected, all your neurons would be active all the time
and the signals would be meaningless.<span style="mso-spacerun: yes;"> </span>In
fact, this sort of overactivation in the brain can lead to seizures.<span style="mso-spacerun: yes;"> </span>It’s been shown in numerous cases of epilepsy
that there is some sort of dysfunction of the inhibitory neurons.<span style="mso-spacerun: yes;"> </span>The excitatory neurons have free reign and go
crazy, leading to a seizure.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">How is epilepsy
treated?<span style="mso-spacerun: yes;"> </span>Medications that potentiate the
inhibitory neurons can help, but they activate all inhibitory neurons
throughout the brain, when maybe the problem is more localized to one spot.<span style="mso-spacerun: yes;"> </span>Just as all excitatory neurons is a bad
thing, too much inhibition is also bad and can lead to cognitive side
effects.<span style="mso-spacerun: yes;"> </span>Another treatment is to open up
the patient’s head, try to find the overactive area and cut it out or zap those
neurons with a laser.<span style="mso-spacerun: yes;"> </span>Destroying brain
cells is always a last resort, though.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">In a recent paper published
in <a href="http://www.nature.com/neuro/journal/v16/n6/full/nn.3392.html" target="_blank">Nature Neuroscience by Hunt et al.</a>, the authors propose another potential
treatment: adding new inhibitory neurons into the epileptic brain.<span style="mso-spacerun: yes;"> </span>Like all new medical ideas, the story starts
with mice.<span style="mso-spacerun: yes;"> </span>They can create a model of
human epilepsy in these mice by treating them with a potent drug.<span style="mso-spacerun: yes;"> </span>These epileptic mice have seizures just like
humans do.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Where do you get new
inhibitory neurons?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The researchers obtained
progenitor cells from mice embryos.<span style="mso-spacerun: yes;"> </span>In
other words, these weren’t inhibitory neurons yet, but they were destined to
turn into them as the mice developed.<span style="mso-spacerun: yes;">
</span>They grafted these progenitors into adult epileptic mice in the
<a href="http://cellways.blogspot.com/2012/03/creating-shocking-memories.html" target="_blank">hippocampal</a> region of the brain (a common area for seizures).<span style="mso-spacerun: yes;"> </span>Amazingly, these pre-neurons migrated
throughout the brain region, as far as 1.5 mm (that’s a lot… think about how
small a mouse brain is).<span style="mso-spacerun: yes;"> </span>Then the
progenitors differentiated into inhibitory neurons, as if they were in a normal
developing brain.<span style="mso-spacerun: yes;"> </span>One week later, the
epileptic mice with extra inhibitory neurons had hardly any seizures, whereas
the untreated mice were having about 2 a day.<span style="mso-spacerun: yes;">
</span>Not only that, but the treated mice showed cognitive improvements
compared to the untreated epileptic mice.<span style="mso-spacerun: yes;">
</span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">So they seemed to “cure” the
epileptic mice by giving them some new inhibitory neurons that were able to
make functional connections with the existing neurons.<span style="mso-spacerun: yes;"> </span>This isn’t as invasive as brain surgery and
it’s much more localized than medication.<span style="mso-spacerun: yes;">
</span>If the epilepsy were focused in a different part of the brain, then they
could transplant the cells there instead.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Is this possible to try in
humans?<span style="mso-spacerun: yes;"> </span>Maybe so, but the first problem
is that we can’t take inhibitory progenitor cells from human embryos.<span style="mso-spacerun: yes;"> </span>There are some ethical issues with growing
clones to harvest parts from them.<span style="mso-spacerun: yes;">
</span>However, you could use embryonic stem cells, or induced pluripotent stem
cells.<span style="mso-spacerun: yes;"> </span>Pluri-what?<span style="mso-spacerun: yes;"> </span>Recent technology allows researchers to take
a skin biopsy, do some genetic engineering to these cells and push them back in
developmental time to a stem cell.<span style="mso-spacerun: yes;">
</span>Pluripotent means that these stem cells have the potential to become any
type of cell, like an inhibitory neuron.<span style="mso-spacerun: yes;">
</span>All it takes is turning on the right genes in these cells to push them
to a particular fate, and if that isn’t already known for inhibitory neurons, I
bet it’s not too far off.<span style="mso-spacerun: yes;"> </span>Plus there’s
the benefit that the transplanted cells will have the same genome as all the
patient’s other cells, because they originated from their skin cells.<span style="mso-spacerun: yes;"> </span>Just wait, regenerative medicine is moving ahead
at lightning speed.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-27551402632051479132013-05-17T16:18:00.000-07:002013-05-17T16:21:37.971-07:00Go go gadget extendo filopodia<span style="font-family: Arial,Helvetica,sans-serif;">I’m back from an intense
semester of learning and teaching Developmental Biology.<span style="mso-spacerun: yes;"> </span>One theme that emerged from my studies was
that the development of organisms is centered around gene expression and
cell to cell signaling.<span style="mso-spacerun: yes;"> </span>Often times, one
cell will differentiate into its mature form, and then release a signaling
protein that tells neighboring cells what to develop into.<span style="mso-spacerun: yes;"> </span>For instance, the nervous system is induced
by signals released from the embryonic backbone.<span style="mso-spacerun: yes;"> </span>There are a number of common signals that are
used over and over throughout development, like BMP, Wnt and Shh.</span><br />
<div class="MsoNormal">
<span style="font-family: Arial,Helvetica,sans-serif;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;"><span style="font-family: Arial,Helvetica,sans-serif;"><a href="http://www.nature.com/nature/journal/vaop/ncurrent/full/nature12157.html" target="_blank">A recent paper by Sanders et al.</a>, publishe</span>d in <i>Nature</i>, looked at how distant cells can signal to each other
via the Shh pathway.<span style="mso-spacerun: yes;"> </span>Unfortunately for
Developmental Biology teachers everywhere, Shh stands for Sonic Hedgehog.<span style="mso-spacerun: yes;"> </span>Oftentimes, strange or humorous gene
names like this can be blamed on the fruit fly researchers who first discovered
the gene, but in this case everyone is to blame.<span style="mso-spacerun: yes;"> </span>This gene was originally discovered by
researchers studying fruit fly embryonic development; they named the gene <i style="mso-bidi-font-style: normal;">hedgehog</i> because the mutant embryos had
lots of tiny bristles all over, kind of like a hedgehog.<span style="mso-spacerun: yes;"> </span>The mammalian researchers took it to the next
ridiculous level, by naming the mammalian version of this gene <i style="mso-bidi-font-style: normal;">Sonic Hedgehog</i>. <span style="mso-spacerun: yes;"> </span>The Shh protein is a secreted signal that
binds receptors on other cells, which activate gene expression in the receiving
cell.<span style="mso-spacerun: yes;"> </span>Shh signaling is important for
specifying many different cell fates, such as the different neurons in the
spinal cord, the cells that become the vertebrae, as well as the formation of
the digits of the hand.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Although Shh is secreted
from the cell, it has chemical modifications that make it stick to the plasma
membrane that surrounds the cell that released Shh.<span style="mso-spacerun: yes;"> </span>How then can Shh induce the development of
cells that are located at a distance?<span style="mso-spacerun: yes;">
</span>Well, the answer is by stretching out long cellular extensions with Shh
localized at the tip.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Shh Filopodia</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Sanders et al. did live
imaging of cells in the developing limb of the chicken using fluorescent
proteins.<span style="mso-spacerun: yes;"> </span>They did some genetic trickery
so only a few cells were labeled in red and others in green.<span style="mso-spacerun: yes;"> </span>This way they could detect individual cells
in a sea of unlabeled cells and examine their structure in real time.<span style="mso-spacerun: yes;"> </span>They observed individual cells extending long
protrusions, called filopodia, from the cell bodies.<span style="mso-spacerun: yes;"> </span>These filopodia could stretch long distances (150
micrometers, like 3-5 cell widths) and were dynamic-- retracting and growing
over time.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">How to think about
filopodia?<span style="mso-spacerun: yes;"> </span>Imagine a stretchy balloon
with a stick inside of it.<span style="mso-spacerun: yes;"> </span>If you could
push that stick into the wall of the balloon, the balloon would protrude from
that one spot as the stick pushes it out.<span style="mso-spacerun: yes;">
</span>That is like a filopodia, where the balloon wall is the plasma membrane
and the stick is a protein called Actin.<span style="mso-spacerun: yes;">
</span>Actin forms long chains that can grow, pushing out the membrane in front
of it.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiOEZfhYVygreBNz_82WDbKE0Htw8DaCK28O0LFArcUK15FgDdU5LXyFbdrbnJUqoYYWKTwHtzL7A2Zc_aDkIhgPEwUefmcMz_I3qOZFVhvtI4h8UuBNByn48PibmYkurrVmFKPaMfR-vAe/s1600/Filopodia.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="297" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiOEZfhYVygreBNz_82WDbKE0Htw8DaCK28O0LFArcUK15FgDdU5LXyFbdrbnJUqoYYWKTwHtzL7A2Zc_aDkIhgPEwUefmcMz_I3qOZFVhvtI4h8UuBNByn48PibmYkurrVmFKPaMfR-vAe/s400/Filopodia.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">The thin, string-like extensions from this cell are filopodia and are filled with Actin. Image from proteopedia.org</td></tr>
</tbody></table>
<div class="MsoNormal">
<span style="font-family: Arial;"><br /></span></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The authors then labeled the
Shh protein with another fluorescent marker and saw that it localized to the
tips of filopodia.<span style="mso-spacerun: yes;"> </span>Not only that, but
the filopodia expressing Shh were more stable and did not retract as
often.<span style="mso-spacerun: yes;"> </span>In order for Shh to act as a
signaling molecule, it has to bind a receptor on another cell.<span style="mso-spacerun: yes;"> </span>Using a different color, the authors observed
two co-receptors for Shh localized to filopodia from other cells.<span style="mso-spacerun: yes;"> </span>They even saw filopodia from two different
cells make contact with each other, where one cell expressed Shh and the other expressed
the receptors.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">This is amazing!<span style="mso-spacerun: yes;"> </span>Instead of releasing a signal out of the cell with the hope that it goes to the right place and isn’t degraded, the cells
literally grow to the right place with the signal on their membranes.<span style="mso-spacerun: yes;"> </span>This is like hand delivering a note to your
coworker, rather than making the note into a paper airplane and throwing it in the
direction of their desk.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh697IMTJHKixrKW2N9a8M2xwcCJMb3ik-HJ9e_-oeZsZ5jINIeUKXhKSOVsdkTDIKPYlypZ2s8FFUTinDhF6AiSBw7B9mEOjx2B6p5C40CWvZ_7Cp6-19Mpcm8_2Lnlc34n48KkPVPpTcn/s1600/Shh+long+range+cartoon.png" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="162" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEh697IMTJHKixrKW2N9a8M2xwcCJMb3ik-HJ9e_-oeZsZ5jINIeUKXhKSOVsdkTDIKPYlypZ2s8FFUTinDhF6AiSBw7B9mEOjx2B6p5C40CWvZ_7Cp6-19Mpcm8_2Lnlc34n48KkPVPpTcn/s400/Shh+long+range+cartoon.png" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">This is how I imagine this working. Two cells that are located at a distance, reach out extensions and meet somewhere in the middle. The Shh signal would bind the receptor, causing changes to the pink cell.</td></tr>
</tbody></table>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">A study like this could not
have been done before recent innovations in live imaging and molecular biology
to introduce the fluorescent proteins into the cells.<span style="mso-spacerun: yes;"> </span>The filopodia are not preserved during the
more traditional, static method of fixing cells with formaldehyde and then
staining them.<span style="mso-spacerun: yes;"> </span>Who knows what other
tricks live cells use during embryonic development.<span style="mso-spacerun: yes;"> </span>I suspect this is only the beginning.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-36091870814045563862013-02-03T21:29:00.000-08:002013-02-03T21:33:55.329-08:00Swapping eggs<div class="MsoNormal">
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--</style><span style="font-family: Arial;">This week’s paper describes
a new technique that could be used to manipulate human oocytes (i.e. eggs) to
prevent a group of diseases called mitochondrial diseases.<span style="mso-spacerun: yes;"> </span>The paper was presented by <a href="http://www.nature.com/nature/journal/v493/n7434/full/nature11647.html" target="_blank">Tachibana et al. in Nature</a> along with a similar paper by Paull et al.<span style="mso-spacerun: yes;"> </span>For the sake of brevity, I will only discuss
the findings from the first paper.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Mitochondria</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">So what are mitochondria?<span style="mso-spacerun: yes;"> </span>Mitochondria are little compartments in the
cell that make cellular energy.<span style="mso-spacerun: yes;"> </span>They
convert the energy stored in food into an energy source that the cell can use
to drive chemical reactions.<span style="mso-spacerun: yes;"> </span>In other
words, they are absolutely essential for our survival.<span style="mso-spacerun: yes;"> </span>The oxygen that we breathe in goes to the
mitochondria to aid in this energy conversion, and we all know how vital oxygen
is.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">There are two other
interesting facts about mitochondria that relate to our story:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">1) All the mitochondria in
our body are duplicates of the mitochondria that were in our mother’s egg.<span style="mso-spacerun: yes;"> </span>In other words, embryonic mitochondria are
not made from our genomic DNA (gDNA) or from sperm contributions.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">2) Mitochondria have their
own DNA , which directs the synthesis of proteins that are necessary for their
function.<span style="mso-spacerun: yes;"> </span>This DNA is known as
mitochondrial DNA (mtDNA) and it is only inherited from the mother, since all
mitochondria originate from the egg.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">If there are mutations in
the mtDNA, then this can lead to problems with the synthesis of cellular
energy, which can lead to human diseases known as mitochondrial diseases.<span style="mso-spacerun: yes;"> </span>There are different types of mutations, which
can affect people in different ways and with differing severities.<span style="mso-spacerun: yes;"> </span>In this paper, the authors propose a way to
prevent mitochondrial diseases from being inherited from generation to
generation.<span style="mso-spacerun: yes;"> </span>Let’s see how that works.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Nuclear transplantation</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Let’s say you have a female
patient with a mitochondrial disease, who wants to have a healthy child.<span style="mso-spacerun: yes;"> </span>She is guaranteed to pass this disease on to
her child via the mitochondria in her oocytes.<span style="mso-spacerun: yes;">
</span>However, most of what makes the child “hers” is what lies in the mother’s
genomic DNA, not in the mitochondrial DNA.<span style="mso-spacerun: yes;">
</span>What if you could take the mother’s genomic DNA (plus the DNA from the
father) and stick it into a healthy “enucleated” oocyte from a donor who has
good, functioning mitochondria?<span style="mso-spacerun: yes;"> </span>All the
genomic DNA will have to be cleared out of the donated oocyte first, creating
an enucleated egg. <span style="mso-spacerun: yes;"> </span>The embryo that
results from this nuclear transplantation will have genomic DNA from its mother
and father, but its mitochondria will originate from the donor oocyte.<span style="mso-spacerun: yes;"> </span>This would circumvent the mutated mtDNA that
is in the real mother’s oocyte.</span><br />
<br />
</div>
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<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKO8yWe-7HbpZbjxcB48bpe451nP6KjXXzWbD97D48pUpjXOVo3cFjlUa_tZ7aHLWVm-q2OSkuOqAPpbMlKs5XGOFwpLRWzt-RaH9_utcX272DafIbeQh-ULklqYsYFNexqVvWOAJ0EsdX/s1600/oocyte+transplant.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="442" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEiKO8yWe-7HbpZbjxcB48bpe451nP6KjXXzWbD97D48pUpjXOVo3cFjlUa_tZ7aHLWVm-q2OSkuOqAPpbMlKs5XGOFwpLRWzt-RaH9_utcX272DafIbeQh-ULklqYsYFNexqVvWOAJ0EsdX/s640/oocyte+transplant.jpg" width="640" /></a></div>
<span style="font-family: Arial;"><br /></span></div>
<div class="separator" style="clear: both; text-align: center;">
</div>
<div class="MsoNormal">
<span style="font-family: Arial;">Tachibana et al. obtained
human oocytes from volunteers and transfered the genomic DNA from one into
another.<span style="mso-spacerun: yes;"> </span>They then injected these
oocytes with sperm DNA (like during real fertilization) and observed what
happened.<span style="mso-spacerun: yes;"> </span>Some oocytes failed to be
fertilized and others died soon after, but a handful of oocytes survived into
the blastula stage of development.<span style="mso-spacerun: yes;"> </span>You
can’t really grow a human embryo in a dish beyond the blastula stage and they
are not allowed (yet) to implant these into women, so we don’t know what would
happen to a child born from this procedure.<span style="mso-spacerun: yes;">
</span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">They did carry out the above
scenario with monkeys.<span style="mso-spacerun: yes;"> </span>They transplanted
the genomic DNA from one oocyte into another and implanted the blastula into
another female monkey who carried the embryo to term.<span style="mso-spacerun: yes;"> </span>The monkey youths are 3 years old now and
doing just fine.<span style="mso-spacerun: yes;"> </span>Their maternal genomic
DNA is from one mother and their mitochondria are from a different oocyte
donor.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Isn’t this amazing?<span style="mso-spacerun: yes;"> </span>I seriously doubt this procedure will be
approved for human use anytime soon, because it’s too much like cloning, which
basically follows the same procedure of putting genomic DNA into an enucleated
egg.<span style="mso-spacerun: yes;"> It's a cool idea, though. </span></span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-68980872160333358742013-01-25T09:42:00.000-08:002013-01-25T09:45:57.293-08:00Isolation and drug addiction<span style="font-family: Arial; font-size: normal;">We
all know that adverse, early life experiences can affect normal development and
the ability to lead a happy and healthy adult life. A number of recent studies have shown that
rodents which are mistreated as pups have long lasting changes to their gene expression
(i.e. <a href="http://www.cellways.blogspot.com/2012/03/take-two-hdac-inhibitors-and-call-me-in.html" target="_blank">epigenetics</a>). They are more
anxious and have a harder time forming new memories. <a href="http://www.cell.com/neuron/abstract/S0896-6273%2812%2901037-9" target="_blank">A paper this week in Neuron</a> builds upon these
results, by studying the effects of social isolation on the “reward pathway” in
the brain. </span><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">Reward
pathway</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">What
is a reward pathway?<span style="mso-spacerun: yes;"> </span>Deep in the brain
is a region known as the ventral tegmental area (VTA), which makes connections
to the nucleus accumbens and prefrontal cortex.<span style="mso-spacerun: yes;">
</span>When we do something that is naturally good, like eating or sex, the
neurons in the VTA release dopamine onto the nucleus accumbens and we interpret
that as “feeling good”.<span style="mso-spacerun: yes;"> </span>This is our
reward for doing something that will help us survive and procreate.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXOivvT6b2tv09Tbp3gOh7DZFzW__B0Ja6VOVNzwZ3TluKAAXdgPaaZmykgT3IophYY2fFMEhMaMcwz-kxY5ZSyZAXOWFgbFWnmA_NWulUdyq3cfyVTqOnOY2HnQCeyywwyneJwbujOm_w/s1600/Reward+pathway+(brainfacts.org).jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="225" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgXOivvT6b2tv09Tbp3gOh7DZFzW__B0Ja6VOVNzwZ3TluKAAXdgPaaZmykgT3IophYY2fFMEhMaMcwz-kxY5ZSyZAXOWFgbFWnmA_NWulUdyq3cfyVTqOnOY2HnQCeyywwyneJwbujOm_w/s400/Reward+pathway+(brainfacts.org).jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">The Reward Pathway in a brain cross section (from brainfacts.org)</td></tr>
</tbody></table>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">Many
drugs of abuse like cocaine, amphetamines and alcohol increase the amount of
dopamine signaling in this pathway; this is one reason why drugs produce a
“high”.<span style="mso-spacerun: yes;"> </span>When this pathway gets
overstimulated by increased drug use, the brain will try to compensate by
making the pathway less efficient.<span style="mso-spacerun: yes;"> </span>This
is why drug users feel depressed when not on drugs and why higher and higher
concentrations of drugs are necessary to produce the same high feeling.<span style="mso-spacerun: yes;"> </span>This is a neurological explanation for drug
addiction.<span style="mso-spacerun: yes;"> </span>Drug abusers also start to
make connections in their lives, and in their brains, between environments (a
certain room, certain people, etc) and the feeling of reward.<span style="mso-spacerun: yes;"> </span>Getting sober is so difficult because the
brain has to unlearn these connections and the reward system has to recover
back to its normal level of activity.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">Plasticity</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">Before
we talk about the paper, I need to introduce one more concept.<span style="mso-spacerun: yes;"> </span>Neurons become activated when channels in
their membranes open and positive ions rush in.<span style="mso-spacerun: yes;">
</span>They can then pass on this signal to another neuron by releasing
neurotransmitters (like dopamine) onto the next neuron.<span style="mso-spacerun: yes;"> </span>The activity in the neuron and the amount of
transmitter it releases into the synapse can change over time, based on that
neuron’s previous experiences.<span style="mso-spacerun: yes;"> </span>This is
known as synaptic plasticity.<span style="mso-spacerun: yes;"> </span>There are
short-term changes, like facilitation, and longer-term changes (we’re talking
hours and days here).<span style="mso-spacerun: yes;"> </span>One of the more
famous types of long-term plasticity is called long term potentiation (LTP) and
is thought to underlie learning and memory.<span style="mso-spacerun: yes;">
</span>When drug users start to become addicted, these types of long term
changes to neuronal activity are occurring throughout the reward pathway.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">Social
isolation and VTA neurons</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">The
experiment begins when young male rats were either housed together in groups of
3 or alone.<span style="mso-spacerun: yes;"> </span>The researchers then
recorded neuronal activity of VTA neurons under various conditions.<span style="mso-spacerun: yes;"> </span>They found that rats that were isolated for
more than 3 weeks, specifically during the equivalent of the rats’ early
adolescence, can more easily induce LTP in the VTA neurons.<span style="mso-spacerun: yes;"> </span>In other words, rats that had no social
interactions during a critical period had more sensitive VTA neurons.<span style="mso-spacerun: yes;"> </span>That is to say, their reward pathway is
primed to be overstimulated, just like during repeated drug use.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">What
are the behavioral manifestations of having a sensitive reward pathway?<a href="http://www.blogger.com/blogger.g?blogID=7550377240327011197" name="_GoBack"></a></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">The
next set of experiments they did is called conditioned place preference.<span style="mso-spacerun: yes;"> </span>The rats were placed in a cage that had two
different compartments, with different wall colors and floor textures.<span style="mso-spacerun: yes;"> </span>The rats were then injected with amphetamine
in one of those particular compartments, so they learned to associate the drug
high with that environment.<span style="mso-spacerun: yes;"> </span>The rats were
then given a choice between the two compartments and inevitably they went to
the room that was associated with the drug.<span style="mso-spacerun: yes;">
</span>The researchers found that isolated rats had a greater preference for
the drug room and developed the preference sooner than the control rats.<span style="mso-spacerun: yes;"> </span>Social isolation as an adolescent causes an
increased rate of learning an association between drugs and environment.<span style="mso-spacerun: yes;"> </span>This could make these rats more vulnerable to
drug addiction.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">What
about unlearning the drug association?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">After
the drug testing, the rats were exposed repeatedly to the drug room, but this
time they didn’t receive any drugs.<span style="mso-spacerun: yes;"> </span>This
is called extinction of a memory and it is measured by the rats losing their
preference for the former drug compartment.<span style="mso-spacerun: yes;">
</span>Socially isolated animals had a significantly slower rate of unlearning
the preference.<span style="mso-spacerun: yes;"> </span>Their memory was more
resistant to extinction.<span style="mso-spacerun: yes;"> </span>If their VTA
neurons are overly sensitive, then it may be harder to rewrite that connection
in the brain between environment and reward.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-family: "Times New Roman";">In
the context of drug addiction, these findings are big.<span style="mso-spacerun: yes;"> </span>An adverse early adolescence can prime the
brain to develop addiction more easily and make it harder to sober up.<span style="mso-spacerun: yes;"> </span>If the VTA neurons start firing every time
you go through an environment associated with drugs, you’re going to want to
take a hit again.<span style="mso-spacerun: yes;"> </span>The authors bring up
an interesting point that social isolation generally causes a depression of
neuronal activity in places like the hippocampus (the site of learning), so
maybe the increased activity in the VTA is the way for the brain to maintain
some sort of homeostasis – some areas increase, some decrease, but overall the
brain may have normal amounts of activity.<span style="mso-spacerun: yes;">
</span>This is an interesting way of looking at this problem.<span style="mso-spacerun: yes;"> </span>I suspect that social isolation offers little
in the way of rewards, so the reward pathway is trying to compensate by getting
more sensitive. <span style="mso-spacerun: yes;"> </span>It will be interesting
to see if there is also a connection with changes in gene expression.<span style="mso-spacerun: yes;"> </span>The authors explain how the VTA neurons get
overactive, from a cellular point of view, but what actually initiates those
changes?<span style="mso-spacerun: yes;"> </span>And how can social interactions
feed into the biology of the cell?<span style="mso-spacerun: yes;"> </span></span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-66305829083869744212012-12-26T21:51:00.001-08:002013-01-25T09:35:22.339-08:00Burning carbs in the Andes<style>
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</style><span style="font-family: Arial;">I am finally back from a
very busy semester.<span style="mso-spacerun: yes;"> </span>I taught physiology
classes at Mills College and UC Berkeley this semester, so I have been
interested in new topics in human physiology.<span style="mso-spacerun: yes;">
</span>This week’s paper by <a href="http://www.cell.com/current-biology/retrieve/pii/S096098221201264X" target="_blank">Schippers et al. came out recently in Current Biology</a>
and describes adaptations that mice must make in order to live at high
altitude.<span style="mso-spacerun: yes;"> </span>They compared the metabolism
of mice that live at 4000m above sea level in the Andes where the oxygen content of air is
about 13%, to mice at sea level, which contains 21% oxygen.<span style="mso-spacerun: yes;"> </span>We all know from experience that we need
oxygen to survive and it’s harder to exercise at high altitudes, but why do our
bodies actually need oxygen?</span><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Oxygen in cellular
respiration</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Most all physiology can be
explained by the following equation, which describes the process of cellular
respiration:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Glucose + 6 Oxygen (O2) --> 6 Carbon dioxide (CO2) + 6 Water (H2O) + 34 ATP</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Glucose is a simple
carbohydrate (sugar) that we use as a direct energy source.<span style="mso-spacerun: yes;"> </span>Glucose, which is 6 carbons long, gets broken
down step by step in a series of chemical reactions.<span style="mso-spacerun: yes;"> </span>At each step, a little bit of energy is
released by the reaction and that is stored in carrier molecules.<span style="mso-spacerun: yes;"> </span>These carriers then donate the energy in the
form of electrons, which is then harnessed to make another molecule called
ATP.<span style="mso-spacerun: yes;"> </span>ATP is cellular energy.<span style="mso-spacerun: yes;"> </span>The chemical bonds in ATP store high energy
and can be used to drive other cellular reactions, like pumping ions, or the
process that causes muscle contraction.<span style="mso-spacerun: yes;">
</span>Without ATP we die.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">But what does oxygen have to
do with this?<span style="mso-spacerun: yes;"> </span>Well, the electrons that are
donated by the carrier molecules must hop from protein to protein in what is
known as the “electron transport chain”.<span style="mso-spacerun: yes;">
</span>The final electron acceptor is oxygen (O2), which forms water with that
extra electron.<span style="mso-spacerun: yes;"> </span>That’s it.<span style="mso-spacerun: yes;"> </span>That’s why we breathe, that’s why our heart
pumps blood— our tissues need energy (ATP) to perform cellular tasks and in
order to get energy from glucose, we need oxygen to accept the final electron.<span style="mso-spacerun: yes;"> </span>Carbon dioxide is produced as a byproduct and
is removed from the body during exhalation.</span></div>
<div class="MsoNormal">
<br /></div>
<table align="center" cellpadding="0" cellspacing="0" class="tr-caption-container" style="margin-left: auto; margin-right: auto; text-align: center;"><tbody>
<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_GfdFHse7OQ7Dg2LnHXYUGHg9JIS6m3jhRUr0rkzr5XEh14b3fjWgj0y4ui3WQwlL0vYBjkYbsIvNzBk_-F4oE9urfkFZ_BGsvCoZ4nP212m90dQbrcNNAU2HHzrGr0mZTfuP6kmsDiS9/s1600/Overview.gif" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="222" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_GfdFHse7OQ7Dg2LnHXYUGHg9JIS6m3jhRUr0rkzr5XEh14b3fjWgj0y4ui3WQwlL0vYBjkYbsIvNzBk_-F4oE9urfkFZ_BGsvCoZ4nP212m90dQbrcNNAU2HHzrGr0mZTfuP6kmsDiS9/s400/Overview.gif" width="400" /></a></td></tr>
<tr align="justify"><td class="tr-caption"><span style="font-family: Arial,Helvetica,sans-serif;">Glycolysis is anaerobic respiration and does not use oxygen. Note that oxygen is used as the last step of the electron transport chain to make the majority of the ATP.<span style="font-size: xx-small;"> (www.phschool.com/science/biology_place/biocoach/cellresp)</span></span></td></tr>
</tbody></table>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">I should also mention here
that the more our tissues are active and working, the more ATP they need and
the more O2 needs to get to the cells.<span style="mso-spacerun: yes;">
</span>When we exercise our muscles are very active, so that’s why the heart rate
and breathing rate increase; our body needs to intake more oxygen and
distribute it faster to our muscles.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">You can see that oxygen
plays a critical role in our cells, so the mice at high altitudes are going to
have a harder time getting their cellular energy.<span style="mso-spacerun: yes;"> </span>How do they manage to run around when there
is so little oxygen?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Energy sources</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">As I mentioned above, we can
make ATP directly from glucose (a carbohydrate).<span style="mso-spacerun: yes;"> </span>We can also make ATP by using fats as an
energy source.<span style="mso-spacerun: yes;"> </span>There are two differences
between these two energy sources:</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">1) When we use fats as an
energy source, it always requires oxygen.<span style="mso-spacerun: yes;">
</span>Glucose, on the other hand, can make a limited amount of ATP without
oxygen, which is called anaerobic respiration.<span style="mso-spacerun: yes;">
</span>This is useful during short vigorous activity, but we cannot make enough
ATP by anaerobic respiration for sustained exercise.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">2) For a given amount of
oxygen, more ATP is produced from carbohydrates, like glucose, than from
fats.<span style="mso-spacerun: yes;"> </span>However, the amount of ATP created
from a single fat molecule is greater than from a glucose molecule.<span style="mso-spacerun: yes;"> </span>In other words, if you have plenty of oxygen,
you should be burning fats.<span style="mso-spacerun: yes;"> </span>But once
oxygen becomes limiting, either because you’re working so hard, or because
you’re at a high altitude, then carbohydrates should be used.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">Given this information, the
authors hypothesized that the mice at high altitudes will burn more
carbohydrates than mice at sea level.<span style="mso-spacerun: yes;">
</span>They have a limited amount of oxygen in the air, so they need to use it
in the most efficient way to produce the energy they need.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">High altitude mice burn more
carbohydrates, but fatigue sooner</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The authors did all their
tests in the same experimental conditions, with the same amount of oxygen in
the air for both sets of mice.<span style="mso-spacerun: yes;"> </span>Under
normal oxygen conditions and when there was low oxygen content, the high
altitude mice burned more carbohydrates than the other mice during moderate
exercise.<span style="mso-spacerun: yes;"> </span>At rest, they also burned more
carbohydrates under low oxygen conditions.<span style="mso-spacerun: yes;">
</span>The authors found that the activity of enzymes associated with breaking
down carbohydrates were greater in the high altitude mice, specifically in the
heart muscles.<span style="mso-spacerun: yes;"> </span>The heart has to work
harder at high altitude to get enough oxygen to the tissues, so it makes sense
that these muscles, in particular, would be burning carbohydrates
preferentially.<span style="mso-spacerun: yes;"> </span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The high altitude mice, therefore,
have adapted to the low oxygen environment by having more active enzymes to
break down carbohydrates rather than fats.<span style="mso-spacerun: yes;">
</span>One problem with that, though, is that the carbohydrate storage is less
extensive than fat storage.<span style="mso-spacerun: yes;"> </span>The
researchers found that high altitude mice fatigued more quickly than the sea
level mice, which burned more fats.<span style="mso-spacerun: yes;"> </span>They
suggest that the fast fatigue is a result of using up all the carbohydrate
stores.<span style="mso-spacerun: yes;"> </span>These mice, though, don’t travel
long distances and just need short bursts of speed to escape predators.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">I really like how so many
physiological processes can be explained through understanding cellular
respiration.<span style="mso-spacerun: yes;"> </span>It’s so logical that animals
at high altitude need to use oxygen more efficiently, so they use carbohydrates
more for energy.<span style="mso-spacerun: yes;"> </span>It’s simple.</span></div>
Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-80412361839744434292012-09-01T13:05:00.001-07:002012-09-01T13:05:18.682-07:00Cellways on temporary hiatusI will not have time to update this blog this semester since I am teaching four classes plus research. I'll catch up with you again in the winter.<br />
<br />
In the meantime, enjoy this hilarious chemistry comic:<br />
<br />
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglXHWAUmFa_dDjzp-aPBJ0YOEzVqObFrvVuNG8TE_2ub_CuPmcz-jopV7pNFQnB-jGCrRLU5kyUSZ7q-tsssCpZAlgGjn8BhY24H17qdJYMbrhFb0eK_BgkFec8r-KzTAxPf7WStE8k8Tv/s1600/Polar+bear+comic.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="320" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEglXHWAUmFa_dDjzp-aPBJ0YOEzVqObFrvVuNG8TE_2ub_CuPmcz-jopV7pNFQnB-jGCrRLU5kyUSZ7q-tsssCpZAlgGjn8BhY24H17qdJYMbrhFb0eK_BgkFec8r-KzTAxPf7WStE8k8Tv/s320/Polar+bear+comic.jpg" width="314" /></a></div>
<br />Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-18847268686463219452012-08-10T10:38:00.000-07:002012-08-10T10:38:09.505-07:00A biological reason for aging weight gain<br />
<div class="MsoNormal">
<span style="font-family: Arial;">There is a growing epidemic
of obesity in the aging population.<span style="mso-spacerun: yes;"> </span>Of
course a lot of this has to do with our cultural lifestyle, but could there
also be a biological explanation related to the way our bodies age?<span style="mso-spacerun: yes;"> </span>One clue comes from the fact that older lab
mice have a tendency to become obese, without the added influence of fast food
restaurants.<span style="mso-spacerun: yes;"> </span>Although there certainly
are differences in metabolism as you age, the older mice also intake more food;
it’s as if their body isn’t telling them the “I’m full” signal.<span style="mso-spacerun: yes;"> </span>Yang et al examine the biological mechanism
underlying this age-dependent obesity in the <a href="http://www.cell.com/neuron/abstract/S0896-6273%2812%2900530-2" target="_blank">newest edition of <i style="mso-bidi-font-style: normal;">Neuron</i></a>.<span style="mso-spacerun: yes;">
</span></span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">The Hypothalamus</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">There is a region towards
the interior of the brain called the hypothalamus which controls all sorts of
basic physiological parameters.<span style="mso-spacerun: yes;"> </span>For
instance, it sets the body temperature, monitors blood pressure and the water
content of the blood, and initiates the feeling of thirst and hunger.<span style="mso-spacerun: yes;"> </span>There are a group of neurons in the
hypothalamus called POMC neurons, which release a hormone, called a-MSH, which
decreases appetite (the feeling of “I’m done eating”).<span style="mso-spacerun: yes;"> </span>Could it be that these neurons don’t function
properly in older mice, so they aren’t getting enough a-MSH to signal them to
stop eating?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Problems with the POMC neurons</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The authors find that as the
mice get older, their POMC neurons get more negative inside.<span style="mso-spacerun: yes;"> </span>Remember that active neurons fire action
potentials, which are basically short bursts of positive ions rushing into the
cell.<span style="mso-spacerun: yes;"> </span>If the POMC neurons are more negative
than usual, they will have further to go to fire an action potential and will
be less active.<span style="mso-spacerun: yes;"> </span>The older POMC neurons
are in fact much less active and therefore release less a-MSH.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">What makes the older POMC
neurons more negative?<span style="mso-spacerun: yes;"> </span>The authors find
that the neurons are overexpressing a potassium channel (K channel), which will
mean there are more open pores in the membrane for K to escape the cell.<span style="mso-spacerun: yes;"> </span>As the positive K ions leave the neuron, it
will make the inside more negative.<span style="mso-spacerun: yes;">
</span>Okay, but why are K channels overexpressed in older neurons?<span style="mso-spacerun: yes;"> </span>Turns out this whole cascade is initiated by
a key signaling protein called TOR.<span style="mso-spacerun: yes;">
</span>Increased TOR levels have been associated with various aspects of aging
before, and an inhibitor of TOR (called rapamycin) can increase the life span
of mice and other animals.<span style="mso-spacerun: yes;"> </span>Check out the
diagram below, which puts all these steps together.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="separator" style="clear: both; text-align: center;">
<a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgsVlPK5S9sqcl5UVMF9wxUwz86U7o_ufCb5_gZYTGQNPSWhG8m98obP4Sd4XVoPfoXNIpLOz5lr6hxsjJN95-5vR-EEJoV8ZU8IkHBS1V3UElz6KuxPA9gED37FeIjF5oJktet0PsYKm-B/s1600/figure+of+pathway.jpg" imageanchor="1" style="margin-left: 1em; margin-right: 1em;"><img border="0" height="121" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEgsVlPK5S9sqcl5UVMF9wxUwz86U7o_ufCb5_gZYTGQNPSWhG8m98obP4Sd4XVoPfoXNIpLOz5lr6hxsjJN95-5vR-EEJoV8ZU8IkHBS1V3UElz6KuxPA9gED37FeIjF5oJktet0PsYKm-B/s640/figure+of+pathway.jpg" width="640" /></a></div>
<div class="MsoNormal">
<span style="font-family: Arial; mso-bidi-font-weight: bold;"><br /></span><span style="font-family: Arial;"></span></div>
<br />
<br />
<div class="MsoNormal">
<span style="font-family: Arial;">Summary: For whatever
reason, POMC neurons overexpress TOR, which makes these neurons less
active.<span style="mso-spacerun: yes;"> </span>They release less of the a-MSH
hormone, so the mice don’t get the “stop eating” signal and continue to intake
food, leading to obesity.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<b><span style="font-family: Arial;">Two complimentary
experiments</span></b></div>
<div class="MsoNormal">
<span style="font-family: Arial;">To test that this pathway is
actually correct, the authors did two complimentary experiments.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">1) If TOR is artificially
increased in young mice (to mimic older mice), will they intake more food and
gain weight?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">2) If TOR levels are
decreased in older mice (to mimic younger mice), will they lose weight?</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">For experiment #1, they
raised TOR levels in young mice by knocking out an upstream inhibitor of
TOR.<span style="mso-spacerun: yes;"> </span>TOR levels are normally controlled
within a certain range by inhibitors, so if you get rid of that inhibition,
there will be more TOR present.<span style="mso-spacerun: yes;"> </span>Over many
weeks, these mutant mice did in fact get fatter than the controls and their
POMC neurons were too negative and didn’t function properly, just like older
mice.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">For experiment #2, they
wanted to decrease TOR in older mice.<span style="mso-spacerun: yes;">
</span>This is actually pretty easy to do by injecting the older mice with the
drug rapamycin, which inhibits TOR (TOR actually stands for Target Of
Rapamycin).<span style="mso-spacerun: yes;"> </span>Rapamycin is made by
bacteria, which were first discovered in soil samples from Easter
Island.<span style="mso-spacerun: yes;"> </span>It is currently
approved for human use, as an immunosuppressant for organ transplant
patients.<span style="mso-spacerun: yes;"> </span>When the older mice were
injected with rapamycin for a few weeks, the POMC neurons came back to life and
fired many action potentials.<span style="mso-spacerun: yes;"> </span>The cells
weren’t so negative because there were less K channels being expressed.<span style="mso-spacerun: yes;"> </span>And yes, rapamycin caused the older mice to
eat less and lose a considerable amount of weight.</span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">So there you have it: rapamycin
is the wonder drug—it will make you live longer and healthier, but there will
be a price to pay with a lowered immune system.<span style="mso-spacerun: yes;">
</span>There may be other ways to tap into this dysfunction in the older POMC
neurons to help prevent midlife obesity.</span></div>Unknownnoreply@blogger.com0tag:blogger.com,1999:blog-7550377240327011197.post-87634549983303905852012-07-20T16:07:00.000-07:002012-07-20T16:07:49.997-07:00Magneto... yes??<span style="font-family: Arial;">A few months ago<a href="http://www.cellways.blogspot.com/2012/04/magnetonope.html" target="_blank"> I wrote about an article</a> that disputed the claim that pigeons have iron-rich cells in
their beaks that sense the earth’s magnetic field. A <a href="http://www.pnas.org/content/early/2012/06/29/1205653109" target="_blank">new paper by Eder et al</a>. in Proceedings of
the National Academy of Sciences describes their discovery of magnetic cells in
the trout nose. </span><br />
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The way they discovered
these cells was pretty ingenious. The
authors took tissue from the trout olfactory epithelium, which is where
chemical odors are sensed, and also where magnetic sensing probably
occurs. They dissociated the cells,
which means they separated them from each other, so they were free to move
about in the liquid culture. Then they
applied an external magnetic field and rotated it around the dish while they
looked at the cells in the microscope.
Out of every 10,000 cells, they observed 1-5 cells that rotated in sync
with the magnetic field. Wow! I can imagine the excitement in the lab when
they first saw a spinning cell. It’s no
wonder that other labs were not able to isolate the magnetic-sensitive cells,
since they are so sparse. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">They noticed that each of
these rotating cells had a dark chunk inside them that could reflect the
microscope light. Upon closer
inspection, this “inclusion” was located right next to the membrane just inside
the cell. They analyzed the elemental
composition of the inclusions and a major component was iron, the only
biological atom that is magnetic. The
authors suspect that the iron is in the form of magnetite (Fe3O4), which has
been found in some bacteria. </span></div>
<div class="MsoNormal">
<br /></div>
<div class="MsoNormal">
<span style="font-family: Arial;">The magnetic inclusions must
be attached to the membrane, because the cells move at the same rate as the
external magnetic field. If the
magnetite were not tethered to the membrane, then it would spin freely in the
intracellular liquid without affecting the rest of the cell.</span></div>
<div class="MsoNormal">
<br /></div>
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<tr><td style="text-align: center;"><a href="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_D1uOcKP-nLlTNfwsBV4e4sAMPPW72OORgkyoCF4rlnKKgcb-w4rLSiwpefDuY9Gbv4sC5yabRPGW7yAzKvM4JSdFIqMt9eiyJjj53tEKWqIwuFxSW3vtxbyoztjjymDpROtAVjWqi8tv/s1600/Rotating+cells.jpg" imageanchor="1" style="margin-left: auto; margin-right: auto;"><img border="0" height="182" src="https://blogger.googleusercontent.com/img/b/R29vZ2xl/AVvXsEi_D1uOcKP-nLlTNfwsBV4e4sAMPPW72OORgkyoCF4rlnKKgcb-w4rLSiwpefDuY9Gbv4sC5yabRPGW7yAzKvM4JSdFIqMt9eiyJjj53tEKWqIwuFxSW3vtxbyoztjjymDpROtAVjWqi8tv/s400/Rotating+cells.jpg" width="400" /></a></td></tr>
<tr><td class="tr-caption" style="text-align: center;">The cell on the left has unattached magnetite (Fe), whereas on the right it is attached to the membrane.</td></tr>
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<span style="font-family: Arial;">How do spinning cells tell
the rest of the trout about the location of the magnetic field? We don’t know, but when the cells are in the
olfactory epithelium in the trout, I’m sure they will not be able to rotate so freely. What happens most likely is that changes to
the magnetic field will cause the magnetite to change positions slightly, which
will tug on the membrane and cause <a href="http://www.cellways.blogspot.com/2012/03/translation-of-touch.html" target="_blank">mechanoreceptors</a> to open. These are ion channels that open or close
when there are mechanical deformations of the membrane (like stretching or
pushing). Once ion channels are
involved, they can “activate” the cell and send signals to cells in the nervous
system, which will relay this information to the brain. Of course, there's no evidence that these particular rotating cells will do that in vivo, but it certainly is a tantalizing start.</span></div>
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<span style="font-family: Arial;"><a href="http://hobbieroth.blogspot.com/2012/07/magnetic-characterization-of-isolated.html" target="_blank">Here is another blogger's take</a> on this same article, but from a physics point of view.</span></div>Unknownnoreply@blogger.com0