Evolutionary biologists are constantly wondering why things are the way they are. I’ve bored you all with a rather esoteric example: Why would a slug lose its ability to learn?
Here’s another one, a little closer to home: Why wouldn’t the human body evolve mechanisms to fight cancer? Why hasn’t natural selection eliminated cancer long ago? Surely a mutation that prevented cancer would confer an advantage. This is pretty puzzling.
First, I have to hasten to say that our bodies DO have cancer fighting mechanisms. Lots of them. They are found at many different levels (molecular, cellular, immune system). These mechanisms do a really good job. It is actually quite amazing that we live so many decades. Such longevity is very rare in nature.
But why do OLD people get cancer more than young ones do? In fact why do old people get feeble at all? In short, why do we senesce? Surely individuals that don’t senesce should be better at surviving that those that do! Makes sense right? If you don’t senesce, you live longer cause you don't die of old age. But if you are smart (which I’m not), you realize that ,,, it depends!
One of the greats of evolutionary biology, George C. Williams realized this back in the 50’s! Williams proposed the idea of antagonistic pleiotropy.
This is a mouthful, but the idea is quite simple. These are genetic “deals with the devil.” If my actuarial table says I am on average going to be eaten by a saber-toothed cat sometime before my 30th birthday, then genes that improve my chances of fighting cancer when I’m in my 80s don’t do my lineage much good. They will not spread very quickly by natural selection.
On the other hand, if a mutation comes along that actually INCREASES my chances of dying of cancer in my 80’s, but, at the same time, ENHANCES my ability to fight saber-tooth tigers during my first 3 decades, this mutation it will have a big advantage. Cause the bad part of the deal (cancer in my 80s) is hardly ever seen (cause I’m usually already eaten by a saber-toothed tiger long before I’m 80), while the good side of the deal is ALWAYS realized. With my new mutation, I, and my descendents, are able to better avoid saber-toothed cats, thereby living on average 5 years longer till the grand ole age of 35 (and produce a couple of more kids). If we happen to be lucky and live to be 80, the devil takes us and we die of cancer. But overall, we have more babies than the lineages that didn’t get to take the deal, so we have more babies. Now each time one of these "deal-with-the-devil" mutations arises, natural selection takes the bait. Thus, lousy genes that kill us when we are old build up. Viola, senescence, i,e., ower fitness when we are old.
Williams posed this possibility as a very logical, very powerful hypothesis. Of course, in science, this doesn’t make it right.
More later.
Thursday, March 25, 2010
Wednesday, March 24, 2010
A Gift
I’ve been given a gift from the gods. I am on sabbatical and my Mom is dying. This means I can arrange my work schedule so I can be with her. Functionally I can help by watching out for her at night. Metaphysically I can process her decline and maybe finally become a grown up.
Because I have to admit I have not really experienced death so much. I was at sea when my dad died. My grandparents’ deaths were pretty much hidden from me. My sweet wife was very much present for each of her two parents’ deaths, but I wasn’t really there. Although watching her live through those passages gave me a sense of what it is all about.
So here I am. I’m using you, mister blog, and you blog readers, as a crutch. Perhaps writing from the perspective of the professor-on-sabbatical that I am supposed to be will give me a stable platform.
Biologically, cancer is a strange affair. It is really all about a cell of your body staging a revolution; reverting to its ancestral state, a single cell trying to grow and divide faster than all the other competing cells in its neighborhood. Somehow, this cell manages to slip past a huge number of checks and brakes put up by your body to prevent this evolutionary reversal. These checks and brakes work very well when we are young, but they tend to wear out as we age. Seems like everything wears out as we age.
Actually, recent research is finding that cancer has a wide variety of forms. Remember me writing about the “transcriptome”? The list of all the genes that are activated in particular cells? Well, cell biologists are now frantically categorizing particular cancers by their transcriptomes. It seems that each clone of cancer cells (e.g., tumor), be it a lymphoma or brain cancer or colon cancer, has its own distinctive transcriptome. The hope is that by characterizing these cancers’ transcriptomes, we can ultimately design therapies, specific to each cancer, that can re-instate the discarded checks and brakes, and stop the cells from their incessant growing and dividing.
Most of you know this, that cancer is a multiheaded monster. Eventually, maybe even in my lifetime, scientists will know enough about how to fashion specific weapons for any ugly headed cancer cell that crops up.
But not in my mom’s lifetime.
Because I have to admit I have not really experienced death so much. I was at sea when my dad died. My grandparents’ deaths were pretty much hidden from me. My sweet wife was very much present for each of her two parents’ deaths, but I wasn’t really there. Although watching her live through those passages gave me a sense of what it is all about.
So here I am. I’m using you, mister blog, and you blog readers, as a crutch. Perhaps writing from the perspective of the professor-on-sabbatical that I am supposed to be will give me a stable platform.
Biologically, cancer is a strange affair. It is really all about a cell of your body staging a revolution; reverting to its ancestral state, a single cell trying to grow and divide faster than all the other competing cells in its neighborhood. Somehow, this cell manages to slip past a huge number of checks and brakes put up by your body to prevent this evolutionary reversal. These checks and brakes work very well when we are young, but they tend to wear out as we age. Seems like everything wears out as we age.
Actually, recent research is finding that cancer has a wide variety of forms. Remember me writing about the “transcriptome”? The list of all the genes that are activated in particular cells? Well, cell biologists are now frantically categorizing particular cancers by their transcriptomes. It seems that each clone of cancer cells (e.g., tumor), be it a lymphoma or brain cancer or colon cancer, has its own distinctive transcriptome. The hope is that by characterizing these cancers’ transcriptomes, we can ultimately design therapies, specific to each cancer, that can re-instate the discarded checks and brakes, and stop the cells from their incessant growing and dividing.
Most of you know this, that cancer is a multiheaded monster. Eventually, maybe even in my lifetime, scientists will know enough about how to fashion specific weapons for any ugly headed cancer cell that crops up.
But not in my mom’s lifetime.
Monday, March 22, 2010
Not in the brochure II
So I’ve been here with Mom for a week plus. I’m here during the nights, Milan, Mom’s caregiver is here during the days.
Mom is very weak, but still very much alive. She has received a steady stream of visitors. They all go away scratching their heads a bit. Mom is on hospice, meaning that she is not relying on medical doctors to help her fight her cancer. There’s way too much of it multiplying way too fast, and her 82 year-old frame cannot take the chemo. But she doesn’t act at all like a dying soul. So her friends leave their from these visits perplexed. They expect to see Death’s cold hand on her, but don't. She is kind of a live wire on a death bed.
But that cold hand is not far away. Her balance is deteriorating daily, her appetite is minimal, her breath is short, and her concentration episodic.
So, we are starting down the waterslide, and this one has no safety net.
Mom is very weak, but still very much alive. She has received a steady stream of visitors. They all go away scratching their heads a bit. Mom is on hospice, meaning that she is not relying on medical doctors to help her fight her cancer. There’s way too much of it multiplying way too fast, and her 82 year-old frame cannot take the chemo. But she doesn’t act at all like a dying soul. So her friends leave their from these visits perplexed. They expect to see Death’s cold hand on her, but don't. She is kind of a live wire on a death bed.
But that cold hand is not far away. Her balance is deteriorating daily, her appetite is minimal, her breath is short, and her concentration episodic.
So, we are starting down the waterslide, and this one has no safety net.
Sunday, March 21, 2010
Not in the brochure
I wrote the following around 10 days ago. I’ve delayed posting it till now.
_______________________________
Here it is, the 10th of March. My mom’s had cancer for 2 years. Now it is starting to get the better of her, as cancer so often does. She’s got it in her spleen, colon, lymph nodes, liver, and lung. That is a significant fraction of the viscera available to take down. She’s 82 years old, and gone through the gauntlet of chemotherapies, and this is where she is.
She is dying. Not today or tomorrow, but maybe next week, or the next week, or the following. We don’t know.
I arrived in Costa Rica, heard her voice on the telephone as she got worse, and realized I was in the wrong place.
I missed my dad’s death. I’m not going to miss my mom’s. I will be there with her. Somehow I have to suppress the dread of empathic recognition, and the palpable feeling of a hole where she will be exiting. Or maybe I can just live in all of it. But I will escort my mom out of here.
On the flight home, I sat on the plane with a young woman whose dad had died 3 years ago of Wegener’s disease. I think that is the name she used. I’ve never heard of it. Neither had she. She had only a few years before been let in on the fact that her mom had multiple sclerosis. So she and her sister and dad were all watching out for mom, when her dad got pneumonia as a consequence of his disease, and up and died. Now her mom is transitioning from barely walking to not walking.
This shit isn’t in the brochure.
I watched a Robert Dinero tear-jerker on the plane out of the corner of my eye. I saw it coming from a long way away and didn’t purchase the earphones; there would have been a flash flood if I had. This is a turbulent time in my life. Not a bucolic sabbatical, but a tumultuous one.
The director of the biological station in Costa Rica had some keen insights to all of this. First he said, “you are doing the right thing”, that is by cutting my research month short at 10 days to assure that I am there when Mom dies. He had missed his mom’s death 40 years previously and is still not over it.
Through all of this, I try not to lose track that this is the natural order of things. The same director also recalled his days in Ghana. There, the death of a parent is a cause for a happy celebration of a natural milestone. By contrast, the death of ones child is considered a dark, dark day. I like this dichotomy. I hope when it is my turn my kids and I can mark my imminent passing in a spirit of celebrating all that is natural.
But all this natural order of things doesn’t much change the hole I’m feeling.
_______________________________
Here it is, the 10th of March. My mom’s had cancer for 2 years. Now it is starting to get the better of her, as cancer so often does. She’s got it in her spleen, colon, lymph nodes, liver, and lung. That is a significant fraction of the viscera available to take down. She’s 82 years old, and gone through the gauntlet of chemotherapies, and this is where she is.
She is dying. Not today or tomorrow, but maybe next week, or the next week, or the following. We don’t know.
I arrived in Costa Rica, heard her voice on the telephone as she got worse, and realized I was in the wrong place.
I missed my dad’s death. I’m not going to miss my mom’s. I will be there with her. Somehow I have to suppress the dread of empathic recognition, and the palpable feeling of a hole where she will be exiting. Or maybe I can just live in all of it. But I will escort my mom out of here.
On the flight home, I sat on the plane with a young woman whose dad had died 3 years ago of Wegener’s disease. I think that is the name she used. I’ve never heard of it. Neither had she. She had only a few years before been let in on the fact that her mom had multiple sclerosis. So she and her sister and dad were all watching out for mom, when her dad got pneumonia as a consequence of his disease, and up and died. Now her mom is transitioning from barely walking to not walking.
This shit isn’t in the brochure.
I watched a Robert Dinero tear-jerker on the plane out of the corner of my eye. I saw it coming from a long way away and didn’t purchase the earphones; there would have been a flash flood if I had. This is a turbulent time in my life. Not a bucolic sabbatical, but a tumultuous one.
The director of the biological station in Costa Rica had some keen insights to all of this. First he said, “you are doing the right thing”, that is by cutting my research month short at 10 days to assure that I am there when Mom dies. He had missed his mom’s death 40 years previously and is still not over it.
Through all of this, I try not to lose track that this is the natural order of things. The same director also recalled his days in Ghana. There, the death of a parent is a cause for a happy celebration of a natural milestone. By contrast, the death of ones child is considered a dark, dark day. I like this dichotomy. I hope when it is my turn my kids and I can mark my imminent passing in a spirit of celebrating all that is natural.
But all this natural order of things doesn’t much change the hole I’m feeling.
Thursday, March 18, 2010
Getting Wet
Allright, enough molecular already. Hopefully you at least got a sense of what we are doing. Something in the brains of Aplysia (California) and Dolabrifera (Costa Rica) is different, because the former learns and the latter doesn’t. We want to find out what. That is the how question.
But we, that is I, also want to figure out why.
This question is much trickier. Why don’t these Dolabrifera show sensitization? Why don’t they learn? Part of coming to Costa Rica is to get insights. How do we do this?
You know what Yogi Berra says, don’t you? You can observe a lot by just watching.
Put your head in their world and just be there. Here is Leonid putting his head into the world of Dolabrifera.
Here is what he sees.
An active, responsive slug. Dolabrifera movements are quicker than those of Aplysia. During low tide in the noon-day sun, these slugs are all over the tidepools doing this. They are anything but dullards. The intuition I get from watching them is that they couldn’t have LOST sensitization, like an absent-minded professor. Rather they would seem to be actively suppressing it. If these slugs were sensitized, a wisp of water current would stop them in their tracks. Reduce them to a little ball of slug jelly. That’s what happens to Aplysia. But Aplysia’s ecology seems much slower paced to me. Maybe they can afford to be a slug ball some of the time. Here’s a representative video from you-tube.
Aplysia in situ
This guy covers much less ground, and his muzzle (called proprodium) is not nearly as quick. He won’t be slowed down much by a strong withdrawal reflex. How bout you all? Do you see any differences that might explain no sensitization in Dolabrifera, and lots of it in Aplysia?
But we, that is I, also want to figure out why.
This question is much trickier. Why don’t these Dolabrifera show sensitization? Why don’t they learn? Part of coming to Costa Rica is to get insights. How do we do this?
You know what Yogi Berra says, don’t you? You can observe a lot by just watching.
Put your head in their world and just be there. Here is Leonid putting his head into the world of Dolabrifera.
Here is what he sees.
An active, responsive slug. Dolabrifera movements are quicker than those of Aplysia. During low tide in the noon-day sun, these slugs are all over the tidepools doing this. They are anything but dullards. The intuition I get from watching them is that they couldn’t have LOST sensitization, like an absent-minded professor. Rather they would seem to be actively suppressing it. If these slugs were sensitized, a wisp of water current would stop them in their tracks. Reduce them to a little ball of slug jelly. That’s what happens to Aplysia. But Aplysia’s ecology seems much slower paced to me. Maybe they can afford to be a slug ball some of the time. Here’s a representative video from you-tube.
Aplysia in situ
This guy covers much less ground, and his muzzle (called proprodium) is not nearly as quick. He won’t be slowed down much by a strong withdrawal reflex. How bout you all? Do you see any differences that might explain no sensitization in Dolabrifera, and lots of it in Aplysia?
Wednesday, March 17, 2010
What's Going On In There?
I first met Leonid at a huge Neuroscience meeting in Atlanta I think. I had read a little of his molecular magic. That is where I first heard the term “transcriptome.” This is similar to a genome, which is the entirety of the genetic material stored in the DNA in the nucleus of the cells of a particular species. The first genome to be sequenced was the human genome, an effort that was HUGELY expensive, but totally cool. Bottom line: a genome represents all the potential genetic instructions of an individual.
By contrast, a transcriptome refers to all the genetic instructions that are actually being sent out to the rest of the cell (by the process known as transcription). Transcriptomes are species specific, but they are also tissue specific, and even cell specific. These instructions represent a subset of the genome, but they also represent what the cell does. For example, the Beta-cells in the islets of Langerhans in your pancreas have one job, and that is to produce lots and lots of insulin to be used by your body. The genome of these Beta-cells is the same as all the other cells in your body, and very close to the now-registered “human genome”. Again, the genome represents genetic potential. But your Beta-cells shut down almost all of those potential genes. Their single function is to make insulin, so it is the insulin gene whose instructions are sent out in huge volumes for manufacture into insulin.
The transcriptome is different from cell to cell. We know that much. We don’t know much about how transcriptomes of particular cells changes across evolution. For example, we don’t know how the transcriptome of different parts of the brain change across evolution.
Here's a part of the brain of an Aplysia (borrowed from Wikipedia). Each little yellow sphere is an individual nerve cell. This is the focus of our research.
By contrast, a transcriptome refers to all the genetic instructions that are actually being sent out to the rest of the cell (by the process known as transcription). Transcriptomes are species specific, but they are also tissue specific, and even cell specific. These instructions represent a subset of the genome, but they also represent what the cell does. For example, the Beta-cells in the islets of Langerhans in your pancreas have one job, and that is to produce lots and lots of insulin to be used by your body. The genome of these Beta-cells is the same as all the other cells in your body, and very close to the now-registered “human genome”. Again, the genome represents genetic potential. But your Beta-cells shut down almost all of those potential genes. Their single function is to make insulin, so it is the insulin gene whose instructions are sent out in huge volumes for manufacture into insulin.
The transcriptome is different from cell to cell. We know that much. We don’t know much about how transcriptomes of particular cells changes across evolution. For example, we don’t know how the transcriptome of different parts of the brain change across evolution.
Here's a part of the brain of an Aplysia (borrowed from Wikipedia). Each little yellow sphere is an individual nerve cell. This is the focus of our research.
Sunday, March 14, 2010
The Seduction of Reduction
So, sensory nerve cells (neurons) in the California sea hare increase their signal strength after they are exposed to serotonin, thereby causing sensitization. Finding this out several decades ago started a furious research effort by a bunch of competing and collaborating laboratories. This discovery is the portal into what Eric Kandel (Nobel Prize, 2000) refers to as the seduction of the reductionist program. Because the next question is how does serotonin do this to sensory neurons? Well there are a slew of special “receptor” proteins all over the outer membrane of sensory neurons, receptors that bind to the serotonin and activate a signal INSIDE the neurons. What kind of a signal? A second messenger called cyclic AMP. On and on this reductionist program meanders, asking more and more mechanistic questions to uncover each of the diverse links that lead to the ultimate increase in signaling that causes the increased withdrawal behavior that is sensitization.
Now many of you have probably glazed over by now, but if you did you’d be making a big mistake. It turns out that a huge number of these links are very similar or identical in YOUR neurons when YOU learn (but if you glazed over, it didn’t happen, so go back and read it again!). Neurobiological research on Aplysia has really pushed forward our understanding of learning and memory. So much so, that the really big researchers in this field are patenting “memory” drugs, based to some extent on the knowledge gleaned from work on this California sea hare.
But here I am in Costa Rica, far from the insanity of biomedically motivated research wanting to know something far more fundamental: How do learning mechanisms change across evolution? This particular example is the disappearance of learning. How did that come to be? To do this we have to go inside the neurons of Dolabrifera and search around for a smoking gun. A difference between Dolabrifera and Aplysia, that can account for the difference in the response of their sensory neurons to serotonin. Or a difference, totally unrelated to the sensory neuron difference, that is the real cause of their lack of sensitization.
This is where Leonid comes in.
Driving into the biological station, San Miguel
Now many of you have probably glazed over by now, but if you did you’d be making a big mistake. It turns out that a huge number of these links are very similar or identical in YOUR neurons when YOU learn (but if you glazed over, it didn’t happen, so go back and read it again!). Neurobiological research on Aplysia has really pushed forward our understanding of learning and memory. So much so, that the really big researchers in this field are patenting “memory” drugs, based to some extent on the knowledge gleaned from work on this California sea hare.
But here I am in Costa Rica, far from the insanity of biomedically motivated research wanting to know something far more fundamental: How do learning mechanisms change across evolution? This particular example is the disappearance of learning. How did that come to be? To do this we have to go inside the neurons of Dolabrifera and search around for a smoking gun. A difference between Dolabrifera and Aplysia, that can account for the difference in the response of their sensory neurons to serotonin. Or a difference, totally unrelated to the sensory neuron difference, that is the real cause of their lack of sensitization.
This is where Leonid comes in.
Driving into the biological station, San Miguel
Saturday, March 13, 2010
The Science of Collaboration
Here’s Leonid coming into the airport in San Jose. This guy is a crazy Russian, in all the right ways. He is incredibly knowledgeable about virtually everything, but not in a Mr-Know-it-all way. Talking science with this guy is just as rich as rich can be.
I invited Leonid to come down to Costa Rica to make sure I correctly processed the brains of my favorite sea hare, Dolabrifera, so that he and his lab collaborators could do modern molecular magic and push forward our understanding of what genetic mechanism might account for this species singular inability to show “sensitization.” Sensitization, you might recall from earlier posts, is when an animal’s withdrawal response to a mild stimulus gets much larger following a “noxious stimulus”, traditionally, a strong electric shock. Sensitization happens in the California sea hare, Aplysia, but is completely lacking in the tropical sea hare, Dolabrifera. Two questions emerge:
What mechanism prevents reflexes in Dolabrifera from getting stronger after an electric shock?
What good does it do Dolabrifera to shed a perfectly good trait that all other sea hares seem to have?
These are the classic how and why questions one can ask of any biological phenomenon. These are where my research on Dolabrifera lies: figuring out how Dolabrifera fails to learn, and figuring out why it fails to learn.
I already have the faintest trace of an answer to both questions. Back in the 90s, my students and I tested 7 different sea slugs for a robust physiological correlate of learning. What the heck is that? Well, it is a careful term to describe something that might be a MECHANISM of learning.
It’s pretty simple, so here goes. Sensory neurons bring information from a light touch to the brain. If the signal is weak, the brain sends out a muscular response that is light. If the signal is strong, the brain says “pull hard”! The theory for what increases the reflex withdrawal in sea hares after they’ve been traumatized, is that the signal from sensory neurons in response to a light tactile stimulus gets much stronger after the animal is traumatized by say electric shock or lobster attack.
How does the sensory neuron tell the brain “pull hard“ when it is getting the same tactile stimulus that made it whisper “pull weak” before the trauma? It is pretty clear that the neurotrasmitter, serotonin is critically involved. When the sea hare is traumatized, this transmitter is released all over the nervous system. Serotonin changes the nervous system in so many ways, we are still making lists. But for our discussion, serotonin’s important effect is to cause sensory neurons that get a weak tactile stimulus to double or triple the strength of their signal to the brain. This makes the sea hare increase the strength and duration of its withdrawal response to the same weak tactile stimulus. Voila, sensitization.
In the 90s, my students and I decided to use neurophysiology to study this sensory response to serotonin in a variety of sea hares. In virtually all species, sensory signaling was increased by serotonin, just like it is in Aplysia californica. But there was one species, embedded in the family tree, whose sensory neurons were completely unchanged by serotonin. You probably guessed the name, Dolabrifera, the very same species we are studying here in Costa Rica.
So now, because of my research in the 90s, we know that Dolabrifera fails to show sensitization, most likely because its sensory neurons fail to respond to serotonin. This is not the end of the mechanistic questions, but rather the beginning. We know that sensory neurons in Dolabrifera don’t respond to serotonin. Now the question is what is it that is changed in Dolabrifera’s brain that prevents its sensory neurons from responding to serotonin?
That is where Leonid come in.
I invited Leonid to come down to Costa Rica to make sure I correctly processed the brains of my favorite sea hare, Dolabrifera, so that he and his lab collaborators could do modern molecular magic and push forward our understanding of what genetic mechanism might account for this species singular inability to show “sensitization.” Sensitization, you might recall from earlier posts, is when an animal’s withdrawal response to a mild stimulus gets much larger following a “noxious stimulus”, traditionally, a strong electric shock. Sensitization happens in the California sea hare, Aplysia, but is completely lacking in the tropical sea hare, Dolabrifera. Two questions emerge:
What mechanism prevents reflexes in Dolabrifera from getting stronger after an electric shock?
What good does it do Dolabrifera to shed a perfectly good trait that all other sea hares seem to have?
These are the classic how and why questions one can ask of any biological phenomenon. These are where my research on Dolabrifera lies: figuring out how Dolabrifera fails to learn, and figuring out why it fails to learn.
I already have the faintest trace of an answer to both questions. Back in the 90s, my students and I tested 7 different sea slugs for a robust physiological correlate of learning. What the heck is that? Well, it is a careful term to describe something that might be a MECHANISM of learning.
It’s pretty simple, so here goes. Sensory neurons bring information from a light touch to the brain. If the signal is weak, the brain sends out a muscular response that is light. If the signal is strong, the brain says “pull hard”! The theory for what increases the reflex withdrawal in sea hares after they’ve been traumatized, is that the signal from sensory neurons in response to a light tactile stimulus gets much stronger after the animal is traumatized by say electric shock or lobster attack.
How does the sensory neuron tell the brain “pull hard“ when it is getting the same tactile stimulus that made it whisper “pull weak” before the trauma? It is pretty clear that the neurotrasmitter, serotonin is critically involved. When the sea hare is traumatized, this transmitter is released all over the nervous system. Serotonin changes the nervous system in so many ways, we are still making lists. But for our discussion, serotonin’s important effect is to cause sensory neurons that get a weak tactile stimulus to double or triple the strength of their signal to the brain. This makes the sea hare increase the strength and duration of its withdrawal response to the same weak tactile stimulus. Voila, sensitization.
In the 90s, my students and I decided to use neurophysiology to study this sensory response to serotonin in a variety of sea hares. In virtually all species, sensory signaling was increased by serotonin, just like it is in Aplysia californica. But there was one species, embedded in the family tree, whose sensory neurons were completely unchanged by serotonin. You probably guessed the name, Dolabrifera, the very same species we are studying here in Costa Rica.
So now, because of my research in the 90s, we know that Dolabrifera fails to show sensitization, most likely because its sensory neurons fail to respond to serotonin. This is not the end of the mechanistic questions, but rather the beginning. We know that sensory neurons in Dolabrifera don’t respond to serotonin. Now the question is what is it that is changed in Dolabrifera’s brain that prevents its sensory neurons from responding to serotonin?
That is where Leonid come in.
Thursday, March 11, 2010
Good Omens
A few days ago I drove down out of the clouds around the Arenal Volcano to pick up my molecular biologist collaborator (and now friend), Leonid Moroz. The drive was hellacious. They had closed the easy road and sent me to the busy busy road, and oh my gosh what a lot of slow trucks on a two lane road.
But I made the 4+ hour trip with at least 5 min to spare. Picked up Leonid, as well as two students (Heather and Sheldon), and headed back west toward the coast. We stayed at a hotel along the way, got up early the next morning, a couple three hours to the ferry and 2 more hours of dirty road, and we finally arrived.
Travelers take notice of omens. This is because there are so many things that can go wrong, and we want to know if something will. Of course add on the importance of good luck in research, and you have at least two very superstitious scientists.
We had omens galore to view. First was the fact that 4 different people coming to the airport by different means (two airplanes, a taxi, and a car) actually defied the odds against the rendezvous, and found each other without mishap.
Second was something that at first blush seemed like a bad omen. At the ferry, my three fellow travelers walked and I drove onto the boat. Lots of backing and filling and brusque ticans waving and shouting. I must admit to being a bit flustered by the operation, but in any case got out of the car and cleverly locked my only keys into the car. Aaargh.
I bet I was the brightest red of reds at that point. I sheepishly approached the “foreman of parking” or whatever they called him, and in my best Spanish explained what happened to my llave. Did I notice a smirk? He pointed me toward a grey-haired gentlemen, and shouted to him something unintelligible (to my ears), although it was perfectly clear what kind of things he might have been saying. “Hey Juan, another bungling tourist locked his keys in the car.” I walked over to Juan who told me to wait a minute.
10 min later Juan returned loaded with tools. A piece of cardboard (to prevent scratching), two good sized screwdrivers, and a magic wire already formed into a little wedge to capture the lock.
What I realized, as this guy miraculously slithered the magic wire into the narrow gap in the door held open by the screwdrivers, was that this apparently bad luck was actually good luck. People probably do this mistake “all the time” on the ferry. Well maybe not all the time, but the point is that because every car blocks out a bunch of other cars, ferries cannot afford to have any car stopped on their deck by some flustered soul locking in his keys. So they have a special guy who breaks into cars very well. If I had locked my keys in the car anywhere else in Costa Rica, it would certainly be many hours before I got back in it again. Bottom line: It was a good omen that I happened to lock my keys in the car in a place where the fix was right at hand.
Here we are, arrived, on the tip of the Nicoya Peninsula, set to start doing some serious science.
But I made the 4+ hour trip with at least 5 min to spare. Picked up Leonid, as well as two students (Heather and Sheldon), and headed back west toward the coast. We stayed at a hotel along the way, got up early the next morning, a couple three hours to the ferry and 2 more hours of dirty road, and we finally arrived.
Travelers take notice of omens. This is because there are so many things that can go wrong, and we want to know if something will. Of course add on the importance of good luck in research, and you have at least two very superstitious scientists.
We had omens galore to view. First was the fact that 4 different people coming to the airport by different means (two airplanes, a taxi, and a car) actually defied the odds against the rendezvous, and found each other without mishap.
Second was something that at first blush seemed like a bad omen. At the ferry, my three fellow travelers walked and I drove onto the boat. Lots of backing and filling and brusque ticans waving and shouting. I must admit to being a bit flustered by the operation, but in any case got out of the car and cleverly locked my only keys into the car. Aaargh.
I bet I was the brightest red of reds at that point. I sheepishly approached the “foreman of parking” or whatever they called him, and in my best Spanish explained what happened to my llave. Did I notice a smirk? He pointed me toward a grey-haired gentlemen, and shouted to him something unintelligible (to my ears), although it was perfectly clear what kind of things he might have been saying. “Hey Juan, another bungling tourist locked his keys in the car.” I walked over to Juan who told me to wait a minute.
10 min later Juan returned loaded with tools. A piece of cardboard (to prevent scratching), two good sized screwdrivers, and a magic wire already formed into a little wedge to capture the lock.
What I realized, as this guy miraculously slithered the magic wire into the narrow gap in the door held open by the screwdrivers, was that this apparently bad luck was actually good luck. People probably do this mistake “all the time” on the ferry. Well maybe not all the time, but the point is that because every car blocks out a bunch of other cars, ferries cannot afford to have any car stopped on their deck by some flustered soul locking in his keys. So they have a special guy who breaks into cars very well. If I had locked my keys in the car anywhere else in Costa Rica, it would certainly be many hours before I got back in it again. Bottom line: It was a good omen that I happened to lock my keys in the car in a place where the fix was right at hand.
Here we are, arrived, on the tip of the Nicoya Peninsula, set to start doing some serious science.
Wednesday, March 10, 2010
Fun and Wild III
The next morning I finally, after all these years, went on a Canopy Zip Line. This ride was apparently invented during the logging days, when loggers would be way up to hell and gone high on a mountain cutting down old-growth giants. At the end of the day they just didn’t feel like struggling down the steep slopes, so they devised these wires, strung from tree to tree, and rode down on a pulley attached to a harness. Nowadays, this is huge business for the tourist industry. I’m guessing property owners can make orders of magnitude more money by zooming tourists over the trees than they do cutting the trees down. So I joined the industry and ante’d up my $45 (all for science you understand).
Once again (like the water slides), a big hunk of the adrenaline is knowing that you aren’t in well protected Disneyland again. You immediately see this is not disneyland any more by the happy and VERY dirty faces of the previous group.
The main assistant (There were three assistants and a photographer) gives us instructions, that were more him making jokes than useful instructions. Up we walk up on a man-made platform at the top of a ridge. Very high. Lots of Texans in the group. Everyone, including me, gasping a little. The guide making more jokes, this time very much more appreciated.
So who goes first? Of course, a guy that had done it before. So very cool to watch him float off the platform down the forest to the next platform. When my turn came, it was really exhilarating. Wind on your face, green everywhere. Just like your best flying dream. I used to do this as a kid from the highest avocado tree in our neighbor’s back yard, but this ride was orders of magnitude higher and faster. We zipped our way down a very high mountain. Here’s a movie of the middle. You can see one guy zipping way up high from right to left, followed by his fiancé coming right into the platform we are sitting on.
This was all fun and games, but everyone knows it isn’t safe. I mean the guides are really experienced. You are never untethered, so you can’t really fall to your death. But one of the women in the group somehow let go of her right hand, which is bad for two reasons. One is that letting go means your head goes down till you grab onto something else. Two is that your right hand is your braking hand. So suddenly we see something not right as Pam zooms toward us waiting at the platform. She has her head down by her knees, and she’s just going REALLY fast. I immediately looked at the guide, and watched him prepare for a “catch”. He braced himself for the collision, and caught her body with his right arm and shoulder and cradled her head with his left hand. Her out of control momentum drove them both back a meter or so. He crashed into the tree trunk (on which the platform was built) a little, but she was unharmed. Scared shitless, but unharmed.
I have never heard of these zip rides in California, I’m guessing because they just aren’t safe enough for our litigious society. But here they are everywhere. Again, the Costa Ricans have imposed layers of security on an otherwise really dangerous ride. But my point is the same. In Costa Rica they work hard to create an illusion of safety, whereas in California they work hard to create the illusion of danger.
Here I am thoroughly enjoying everything, illusions and all.
Once again (like the water slides), a big hunk of the adrenaline is knowing that you aren’t in well protected Disneyland again. You immediately see this is not disneyland any more by the happy and VERY dirty faces of the previous group.
The main assistant (There were three assistants and a photographer) gives us instructions, that were more him making jokes than useful instructions. Up we walk up on a man-made platform at the top of a ridge. Very high. Lots of Texans in the group. Everyone, including me, gasping a little. The guide making more jokes, this time very much more appreciated.
So who goes first? Of course, a guy that had done it before. So very cool to watch him float off the platform down the forest to the next platform. When my turn came, it was really exhilarating. Wind on your face, green everywhere. Just like your best flying dream. I used to do this as a kid from the highest avocado tree in our neighbor’s back yard, but this ride was orders of magnitude higher and faster. We zipped our way down a very high mountain. Here’s a movie of the middle. You can see one guy zipping way up high from right to left, followed by his fiancé coming right into the platform we are sitting on.
This was all fun and games, but everyone knows it isn’t safe. I mean the guides are really experienced. You are never untethered, so you can’t really fall to your death. But one of the women in the group somehow let go of her right hand, which is bad for two reasons. One is that letting go means your head goes down till you grab onto something else. Two is that your right hand is your braking hand. So suddenly we see something not right as Pam zooms toward us waiting at the platform. She has her head down by her knees, and she’s just going REALLY fast. I immediately looked at the guide, and watched him prepare for a “catch”. He braced himself for the collision, and caught her body with his right arm and shoulder and cradled her head with his left hand. Her out of control momentum drove them both back a meter or so. He crashed into the tree trunk (on which the platform was built) a little, but she was unharmed. Scared shitless, but unharmed.
I have never heard of these zip rides in California, I’m guessing because they just aren’t safe enough for our litigious society. But here they are everywhere. Again, the Costa Ricans have imposed layers of security on an otherwise really dangerous ride. But my point is the same. In Costa Rica they work hard to create an illusion of safety, whereas in California they work hard to create the illusion of danger.
Here I am thoroughly enjoying everything, illusions and all.
Tuesday, March 9, 2010
FunAndWildII
The night after my water-slide adventure I stayed at a hotel (Arenal Paraiso) with acres of thermal pools. I wandered around looking for a good pool by myself, to soothe my aching knees (from scrambling over lava during the day). Found a good hot one at the very top. No one else there. Lowered myself in. Felt really good. Started to relax. Started to almost fall asleep.
Suddenly whoa! A snake. In the water. What the hell is it doing here? Then it started swimming toward me! Up I erupted, like a boulder flying out of a crater. Jesus. It was little, but isn’t it the little ones that eat you?
So that’s what I would call a “natural” hot springs, one that has an ecosystem. What if there were white sharks, and part of the fun was your participation in the food web? I went to a lower pool, but somehow I just couldn’t relax much. Here’s a movie peek at two of the well-hidden hotprings. Can you find a snake in the movies? Don’t tell me if you can.
So, would YOU ever expect to find anything alive in a 100-degree pool? No. Never. But that’s California. Here, anything is possible. I can really see how Michael Crichton started his novel Jurassic Park in Costa Rica. If a snake goes hunting for its meal in 100 degrees, anything, including T. rex, is possible.
Suddenly whoa! A snake. In the water. What the hell is it doing here? Then it started swimming toward me! Up I erupted, like a boulder flying out of a crater. Jesus. It was little, but isn’t it the little ones that eat you?
So that’s what I would call a “natural” hot springs, one that has an ecosystem. What if there were white sharks, and part of the fun was your participation in the food web? I went to a lower pool, but somehow I just couldn’t relax much. Here’s a movie peek at two of the well-hidden hotprings. Can you find a snake in the movies? Don’t tell me if you can.
So, would YOU ever expect to find anything alive in a 100-degree pool? No. Never. But that’s California. Here, anything is possible. I can really see how Michael Crichton started his novel Jurassic Park in Costa Rica. If a snake goes hunting for its meal in 100 degrees, anything, including T. rex, is possible.
Thursday, March 4, 2010
Fun and Wild
A few nights ago, I paid money ($39) for dinner and a soak in a hotsprings at the Baldi Hotel (I actually stayed in the Hotel Amistad for $25 dollars!) The Baldi is as ostentatious as you can imagine, but it has lots of hotsprings. And the thing that caught my eye at the tourist information booth when I saw the pictures, is that they have water slides that empty into the hot springs! Really? Water slides at a thermal hotsprings? I drove out there, paid my $39 dollars, ate my dinner a little too quickly, and changed into my bathing suit and started wading around and around and around. People, sidling up to bars, kissing in the shadows, laughing and talking in groups.
Baldi
I, skulking past them, looking for what? Warmer water? A pretty girl? No, the frigging water slides. Eventually I asked, and found they were even farther up the hill. Up I went, and there they were, three giant water slide exits into a giant thermal pool.
I casually slip into the water, a bunch of overweight 50-year old frenchies wading around socializing. I sidle over to the three slide exits, two of them covered tunnels, the third open. Where are the laughing 20-year olds? I saw a bunch down lower. Cmon, isn’t anyone going down this thing? Nope. I asked the apparent guide of the frenchies, is the water slide closed? No, he said, relieved (He was bored to tears, I found out later). You want to try it? Sure.
So up we walk. Up and up. Now it’s been a few years (actually a couple of decades) since I last went down water slides, and they were much smaller than this one. The man, who was a Tico (slang for Costa Rican), LOVED water slides. Oscar was his name. I asked him about this one. Well there is one easy one, one medium wild one, and one really really wild one. Sounds like the set up of a joke, doesn’t it?
Cool. What do you mean really really wild?
Well my first time down it I thought I was going to die.
Oh. Why?
Because it (and the easy one) is completely covered, and especially at night, is pitch pitch black inside. You can’t see the turns coming.
Ok. I’ll go on the easy one.
So, picture yourself me. Here I am, kind of wandering around impulsively doing things till my Russian colleague (Leonid, more later) comes with his molecular biology stuff. Always wanted to see this volcano and here I am about to ride a water slide full of its heated water. In the dark. In a country far, far away, where I know almost no one, and am traveling completely by myself.
But what the hell, right? It’s just a water slide. People don’t die on it, or it wouldn’t be here. So Oscar goes first, and then I go. Seated. Slick new swim trunks on (less friction). My first sensation is that it is just such a rush to accelerate. I can see the first turn and lean into it. Nice. And then the lights go off. Pitch black. I kind of guess which way to bank, and I guess wrong. Almost slam my head on the side of the slide.
Not a video game.
Suddenly steeper, faster. I instinctively lie back, holding my head off the slide bottom. Survival mode. The next few turns scared the piss out of me, no idea where I was, just banging from side to side. Skipped out the exit into the pool of frogs, and just about puked.
Oscar was laughing. How’d you like it? Uh, it was a little much.
You have to get used to it, he said.
So, I went back up, and got used to it. Tried the medium one. Open, so I could see. Very fun. Then I tried that one again, only this time facing down on my belly like superman. Very cool. Like a big body surfing wave. Tried the covered medium one belly down. It was fun too. But I walked away from that scariest one. Why?
Because Costa Rica isn’t like California.
In California, they try to generate fun and wild from a platform of boring safety. They build an illusion of fun and wild. The jungle ride, magic mountain, the matterhorn. All are carefully engineered, with emphasis on careful. Cause if they screw up; if somebody gets hurt; they get sued, big time.
But in Costa Rica, where it seems nobody gets sued, they take very scary things, like boulders shooting down a mountain, and build an illusion of safety. Somebody built a scary water slide. It isn’t safe. It is fundamentally wild. But they present it as if it is a California water slide.
Two more examples tomorrow.
Baldi
I, skulking past them, looking for what? Warmer water? A pretty girl? No, the frigging water slides. Eventually I asked, and found they were even farther up the hill. Up I went, and there they were, three giant water slide exits into a giant thermal pool.
I casually slip into the water, a bunch of overweight 50-year old frenchies wading around socializing. I sidle over to the three slide exits, two of them covered tunnels, the third open. Where are the laughing 20-year olds? I saw a bunch down lower. Cmon, isn’t anyone going down this thing? Nope. I asked the apparent guide of the frenchies, is the water slide closed? No, he said, relieved (He was bored to tears, I found out later). You want to try it? Sure.
So up we walk. Up and up. Now it’s been a few years (actually a couple of decades) since I last went down water slides, and they were much smaller than this one. The man, who was a Tico (slang for Costa Rican), LOVED water slides. Oscar was his name. I asked him about this one. Well there is one easy one, one medium wild one, and one really really wild one. Sounds like the set up of a joke, doesn’t it?
Cool. What do you mean really really wild?
Well my first time down it I thought I was going to die.
Oh. Why?
Because it (and the easy one) is completely covered, and especially at night, is pitch pitch black inside. You can’t see the turns coming.
Ok. I’ll go on the easy one.
So, picture yourself me. Here I am, kind of wandering around impulsively doing things till my Russian colleague (Leonid, more later) comes with his molecular biology stuff. Always wanted to see this volcano and here I am about to ride a water slide full of its heated water. In the dark. In a country far, far away, where I know almost no one, and am traveling completely by myself.
But what the hell, right? It’s just a water slide. People don’t die on it, or it wouldn’t be here. So Oscar goes first, and then I go. Seated. Slick new swim trunks on (less friction). My first sensation is that it is just such a rush to accelerate. I can see the first turn and lean into it. Nice. And then the lights go off. Pitch black. I kind of guess which way to bank, and I guess wrong. Almost slam my head on the side of the slide.
Not a video game.
Suddenly steeper, faster. I instinctively lie back, holding my head off the slide bottom. Survival mode. The next few turns scared the piss out of me, no idea where I was, just banging from side to side. Skipped out the exit into the pool of frogs, and just about puked.
Oscar was laughing. How’d you like it? Uh, it was a little much.
You have to get used to it, he said.
So, I went back up, and got used to it. Tried the medium one. Open, so I could see. Very fun. Then I tried that one again, only this time facing down on my belly like superman. Very cool. Like a big body surfing wave. Tried the covered medium one belly down. It was fun too. But I walked away from that scariest one. Why?
Because Costa Rica isn’t like California.
In California, they try to generate fun and wild from a platform of boring safety. They build an illusion of fun and wild. The jungle ride, magic mountain, the matterhorn. All are carefully engineered, with emphasis on careful. Cause if they screw up; if somebody gets hurt; they get sued, big time.
But in Costa Rica, where it seems nobody gets sued, they take very scary things, like boulders shooting down a mountain, and build an illusion of safety. Somebody built a scary water slide. It isn’t safe. It is fundamentally wild. But they present it as if it is a California water slide.
Two more examples tomorrow.
Wednesday, March 3, 2010
Wild&Fun
So what does wild mean? I’ve been thinking about this question a lot. I’ve also been thinking about fun. What does fun mean?
Yesterday I was over at a National Park trail at the foot of the Volcano Arenal. This thing is a real volcano.
Volcano Photo
It goes up symmetrically, very steep, and its top has been covered by fog all but maybe 15 min of the last 3 days.
But after walking a well-tended National Park trail , you come to the end, where the sign reads don’t go any farther. You hear this funny noise along the way, sounds like wind on the video, but it’s not.
It is the sound of boulders rolling down the volcano, I should say flying down the volcano. Eventually, you notice, way far away on the side of the volcano, a fog rising up. Then, after some practice you see that this is dust not fog, and that it is being kicked up by big mother boulders shooting down the mountain from the top. The noise is the noise of these boulders, distorted by the very long distance away. Check out the video. You won’t see the boulders, but you can see the dust rising where they hit. Really cool. Really wild. If you happened to wander over in that vicinity you would die a terrifying death as you tried to dodge screaming boulders on the sharp lava rock.
So the question of wild is very interesting. Christian, a Tico (Costa Rican) economics major was interviewing people watching the boulders fall. He had interviewed them two years before and was trying to see if the “value” of the experience had changed in the interim. I asked him if it had. He wasn’t sure, or really very interested. But what he WAS interested in was the monkeys.
Two years before there were tons of monkeys. Now they seem to be gone. Christian is convinced that the exponentially increasing traffic on the trail has scared them away. Totally cool hypothesis. This kid should be a biologist, not an economist.
Now those of you who’ve followed my blog might recognize this effect as a strictly behavioral one. These loud tourists have very little impact on the ecology of the area. Just a thin low-relief trail. No changes to the vegetation, or run-off or anything. Just a lot of loud tourists streaming back and forth every day.
But the behavioral effect that Christian observed, probably correct yet completely unproved (because Christian never measured quantitatively the density of the monkeys), is that the monkeys moved away during the last two years.
This is kind of the reverse of the lobster effect inside the reserves at Catalina. There, the imposed protection makes the lobsters more aggressive (via hunger), and thereby changes the ecosystem (our hypothesis, as yet unproven). Here, the lifting of protection may be causing the monkeys to shy away to somewhere else (don’t know what the ecosystem effect is here, but I imagine it is pretty big).
Ecosystem managers tend to think from the bottom up. Maintain the trees and plants intact and everything will be ok. I’m thinking more and more, these days, that this approach leaves a ton of critically important questions about behavioral changes unanswered.
Here’s Christian standing by a big ole tree in the park.
What about the fun you ask?
Stay tuned.
Yesterday I was over at a National Park trail at the foot of the Volcano Arenal. This thing is a real volcano.
Volcano Photo
It goes up symmetrically, very steep, and its top has been covered by fog all but maybe 15 min of the last 3 days.
But after walking a well-tended National Park trail , you come to the end, where the sign reads don’t go any farther. You hear this funny noise along the way, sounds like wind on the video, but it’s not.
It is the sound of boulders rolling down the volcano, I should say flying down the volcano. Eventually, you notice, way far away on the side of the volcano, a fog rising up. Then, after some practice you see that this is dust not fog, and that it is being kicked up by big mother boulders shooting down the mountain from the top. The noise is the noise of these boulders, distorted by the very long distance away. Check out the video. You won’t see the boulders, but you can see the dust rising where they hit. Really cool. Really wild. If you happened to wander over in that vicinity you would die a terrifying death as you tried to dodge screaming boulders on the sharp lava rock.
So the question of wild is very interesting. Christian, a Tico (Costa Rican) economics major was interviewing people watching the boulders fall. He had interviewed them two years before and was trying to see if the “value” of the experience had changed in the interim. I asked him if it had. He wasn’t sure, or really very interested. But what he WAS interested in was the monkeys.
Two years before there were tons of monkeys. Now they seem to be gone. Christian is convinced that the exponentially increasing traffic on the trail has scared them away. Totally cool hypothesis. This kid should be a biologist, not an economist.
Now those of you who’ve followed my blog might recognize this effect as a strictly behavioral one. These loud tourists have very little impact on the ecology of the area. Just a thin low-relief trail. No changes to the vegetation, or run-off or anything. Just a lot of loud tourists streaming back and forth every day.
But the behavioral effect that Christian observed, probably correct yet completely unproved (because Christian never measured quantitatively the density of the monkeys), is that the monkeys moved away during the last two years.
This is kind of the reverse of the lobster effect inside the reserves at Catalina. There, the imposed protection makes the lobsters more aggressive (via hunger), and thereby changes the ecosystem (our hypothesis, as yet unproven). Here, the lifting of protection may be causing the monkeys to shy away to somewhere else (don’t know what the ecosystem effect is here, but I imagine it is pretty big).
Ecosystem managers tend to think from the bottom up. Maintain the trees and plants intact and everything will be ok. I’m thinking more and more, these days, that this approach leaves a ton of critically important questions about behavioral changes unanswered.
Here’s Christian standing by a big ole tree in the park.
What about the fun you ask?
Stay tuned.
Monday, March 1, 2010
Wrong-footing Around
1Mar10
Wrong-footing around.
Came into San Jose, Costa Rica, near midnight night before last. To bed at the Hampton Inn. Slept like a log. Awakened by telephone. The delivery of my little 4X4, rented for the entire 4 weeks.
Everything is out of balance. My Spanish sucks. My sense of what the hell I am doing is very unfocused. Bad combination.
Just a scant week before coming here, out of the blue, I got an email from the Costa Rican fellow who was so instrumental in organizing a travel course I co-taught here 4 or 5 years ago. It was an intensive 3-week course with 13 students; TONS of logistics, a half-dozen different places we bused or floated to. It was really cool, but also very hard work, and I vowed never to do it again unless someone else did ALL the organizing. I even told Jose as much.
So literally days before I was to come to Costa Rica, and literally years since we last corresponded, Jose sends me an email, completely out of the blue, telling me he is ready to call my bluff and organize a travel course from top to bottom. I write back and say I’ll be there in a couple of days, can we meet.
Yesterday, Jose swept into the lobby of the Hampton Inn, and escorted me back into the real Costa Rica. The epitome of Costa Rica is that nobody uses street names. They use landmarks. Addresses are simply a hierarchical series of landmarks. Very confusing. Very wrong-footed. Especially for an entity such as Google Earth! When I looked up Hampton Inn on Google earth, I found no less than half a dozen in the airport area alone! Which one was I in?!
Of course, I neglected to consider that Google Earth could get anything wrong. That the descriptive algorithm of landmarks means ambiguity, a quality that makes computer algorithms burn up. There is only one Hampton Inn near the airport.
Jose got there early. He came with his sister and her husband. We reminisced and gossiped in the lobby, and Jose recommended a good side-trip to one of the volcano rain-forests, and even called a local lodge there. He was about to send me on my way, when I said, whoa. I want to see your new school! Cmon, Jose. Let’s go see it.
Wrong-footed in the right direction.
Subscribe to:
Posts (Atom)
