Constitutive formation of caveolae in a bacterium.
October 18, 2012 2:55 AM Subscribe
Constitutive formation of caveolae in a bacterium. [Full Text]
Caveolin plays an essential role in the formation of characteristic surface pits, caveolae, which cover the surface of many animal cells. The fundamental principles of caveola formation are only slowly emerging. Here we show that caveolin expression in a prokaryotic host lacking any intracellular membrane system drives the formation of cytoplasmic vesicles containing polymeric caveolin. Vesicle formation is induced by expression of wild-type caveolins, but not caveolin mutants defective in caveola formation in mammalian systems. In addition, cryoelectron tomography shows that the induced membrane domains are equivalent in size and caveolin density to native caveolae and reveals a possible polyhedral arrangement of caveolin oligomers. The caveolin-induced vesicles or heterologous caveolae (h-caveolae) form by budding in from the cytoplasmic membrane, generating a membrane domain with distinct lipid composition. Periplasmic solutes are encapsulated in the budding h-caveola, and purified h-caveolae can be tailored to be targeted to specific cells of interest.Elio Schaechter writes in plain English about how fantastically amazing and unexpected the researchers actually pulling this off is, and he also talks about it in more detail in his podcast.
Consider the possibilities for drug delivery... In another proof-of-principle step, these researchers showed that caveolae containing GFP and an immunoglobulin-binding domain from staph Protein A not only became bound to human breast cancer cells carrying an antibody on their surface but appeared to become internalized. ... It appears that this could become a formidable tool for cancer chemotherapy and for other conditions that may be ameliorated by the targeting of specific proteins.
posted by Segundus at 3:46 AM on October 18, 2012 [1 favorite]
posted by Segundus at 3:46 AM on October 18, 2012 [1 favorite]
So living organisms are divided between the Bacteria, the Archaea, and the Eukaryotes. We are Eukaryotes along with other animals, plants, the yeasts that make beer and bread, Giardia, and the amoebae being infected in my last post. We are all grouped together by a number of common features that in theory we all share but neither bacteria nor archaea do. Back in the 70s this three domain system was created when we realized that Bacteria and Archaea were as unalike from each other as we were from the both of them. However, what were once clear and absolute divisions have become fuzzy and better described as rules that are always the case except for the times it isn't.
posted by Blasdelb at 3:55 AM on October 18, 2012 [7 favorites]
The biggest defining feature of Eukaryotes is the presence of a nucleus. It is what the name means in Greek; Eu-Karyon or with seed. However we have since found bacteria with features that are awfully hard not to describe as nuclei.This also has all kinds of potential applications in research, medicine, industrial microbiology, and environmental microbiology. It totally changes our perception of what can be fitted into a bacterial cell.
Next is the presence of endosymbionts. However we have found Eukaryotes that don't have them, even if there is genomic evidence that they were once there and lost.
Next are cytoskeletal proteins. However its now pretty clear that bacteria have their own cytoskeletons and rough analogues of all of the kinds of components that Eukaryotes do and then some, even if their purposes tend to be a bit different.
Some might point to the Cell Walls of plants, but they are only in plants and have pretty close analogues in the peptidoglycan layer of Gram +ve bacteria.
Really the remaining particularly solid morphological difference was the ability to endocytose, and this paper totally just showed that bacteria can be prodded into doing that with just one Eukaryotic protein. What gets me is how easy it was for them, the effort being almost trivial, and how dramatically it worked.
posted by Blasdelb at 3:55 AM on October 18, 2012 [7 favorites]
"Consider the possibilities for drug delivery... In another proof-of-principle step, these researchers showed that caveolae containing GFP and an immunoglobulin-binding domain from staph Protein A not only became bound to human breast cancer cells carrying an antibody on their surface but appeared to become internalized. ... It appears that this could become a formidable tool for cancer chemotherapy and for other conditions that may be ameliorated by the targeting of specific proteins."
I hope the post hasn't suggested that this could be the cure for cancer, though it does look like it could maybe be a valuable tool in helping to cure some cancers. Generally the hard part in treating cancer is not killing cancer cells but killing them without killing healthy cells. What makes this such an incredibly difficult problem is how very similar cancer cells are to your cells, and it is because they are your cells - just fucked up. We already have a wide array of really effective ways to kill cells that we can target with highly specific antibodies. This kind of thing could potentially be a really great addition to that arsenal but what we need most are targeting systems, which are much more difficult to pull off outside of a lab.
posted by Blasdelb at 4:02 AM on October 18, 2012
I hope the post hasn't suggested that this could be the cure for cancer, though it does look like it could maybe be a valuable tool in helping to cure some cancers. Generally the hard part in treating cancer is not killing cancer cells but killing them without killing healthy cells. What makes this such an incredibly difficult problem is how very similar cancer cells are to your cells, and it is because they are your cells - just fucked up. We already have a wide array of really effective ways to kill cells that we can target with highly specific antibodies. This kind of thing could potentially be a really great addition to that arsenal but what we need most are targeting systems, which are much more difficult to pull off outside of a lab.
posted by Blasdelb at 4:02 AM on October 18, 2012
Elio Schaechter writes in plain English about how fantastically amazing and unexpected the researchers actually pulling this off is
But he also gives credit to the bacteria:
"The E. coli used in these experiments performed spectacularly, beyond any researchers dreams."
These bacteria were the shit.
posted by three blind mice at 4:24 AM on October 18, 2012
But he also gives credit to the bacteria:
"The E. coli used in these experiments performed spectacularly, beyond any researchers dreams."
These bacteria were the shit.
posted by three blind mice at 4:24 AM on October 18, 2012
What if I told you that engineering a single protein into E. coli is sufficient to make it fill up with membrane-bound vesicles?
I don't know which depresses me more. The number of biochemists I meet who find the notion of emergent properties surprising, or the fact that, despite all the evidence, I keep thinking that just over the next hill I will find myself in the land of biochemists who aren't surprised by the notion of emergent properties.
posted by Kid Charlemagne at 4:35 AM on October 18, 2012 [2 favorites]
I don't know which depresses me more. The number of biochemists I meet who find the notion of emergent properties surprising, or the fact that, despite all the evidence, I keep thinking that just over the next hill I will find myself in the land of biochemists who aren't surprised by the notion of emergent properties.
posted by Kid Charlemagne at 4:35 AM on October 18, 2012 [2 favorites]
I keep thinking that just over the next hill I will find myself in the land of biochemists who aren't surprised by the notion of emergent properties.
Well, that's the thing. Emergence is one of those weird areas at the intersection of math and philosophy - it pops up in everything from computer networking to biochemistry, and it's almost always surprising. It's counterintuitive to human experience, and so it seems weird or wrong or amazing. I mean, look at this - are you not even a little bit amazed, even recognizing it's just an emergent property of a gas vortex?
posted by Slap*Happy at 5:04 AM on October 18, 2012
Well, that's the thing. Emergence is one of those weird areas at the intersection of math and philosophy - it pops up in everything from computer networking to biochemistry, and it's almost always surprising. It's counterintuitive to human experience, and so it seems weird or wrong or amazing. I mean, look at this - are you not even a little bit amazed, even recognizing it's just an emergent property of a gas vortex?
posted by Slap*Happy at 5:04 AM on October 18, 2012
--I hope the post hasn't suggested that this could be the cure for cancer--
I don't think you did that Blasdelb, but there's a tendency, nay, a rule in scientific write-ups, that oneought to must have an all-encompassing, rainbow-shitting, cancer-curing outlook so as to secure funding for the next project and then the next one. I'm not saying this isn't significant, but that particular rosy optimism has a familiar ring to it. I always thought that the magic-bullet antibodies would be the flying cars of the cancer world. They do have a minor place in the arsenal against a few specific cancer types, as I recall. Thanks for the post!
posted by peacay at 5:17 AM on October 18, 2012
I don't think you did that Blasdelb, but there's a tendency, nay, a rule in scientific write-ups, that one
posted by peacay at 5:17 AM on October 18, 2012
"I don't know which depresses me more. The number of biochemists I meet who find the notion of emergent properties surprising, or the fact that, despite all the evidence, I keep thinking that just over the next hill I will find myself in the land of biochemists who aren't surprised by the notion of emergent properties."
Oh come on, some emergent properties are more surprising than others. In the textbook I taught out of last year, it devotes two paragraphs to explaining how bacteria have never been found to do anthing like this and then elaborating on intricately described, and indeed plausible, physiological reasons why endocytosis was probably incompatible with bacterial membranes. Until now we had never seen endocytosis in bactera at all, period, and had even recently seen bizarre and convoluted ways to get around needing to do it.
Are you suggesting that you have expected lipoproteins anchoring the hard, rigid, peptidoglycan to the inner membrane to not interfere? Much less without any intervention like a detergent or deletion mutation to actively address their presence?
posted by Blasdelb at 5:19 AM on October 18, 2012 [1 favorite]
Oh come on, some emergent properties are more surprising than others. In the textbook I taught out of last year, it devotes two paragraphs to explaining how bacteria have never been found to do anthing like this and then elaborating on intricately described, and indeed plausible, physiological reasons why endocytosis was probably incompatible with bacterial membranes. Until now we had never seen endocytosis in bactera at all, period, and had even recently seen bizarre and convoluted ways to get around needing to do it.
Are you suggesting that you have expected lipoproteins anchoring the hard, rigid, peptidoglycan to the inner membrane to not interfere? Much less without any intervention like a detergent or deletion mutation to actively address their presence?
posted by Blasdelb at 5:19 AM on October 18, 2012 [1 favorite]
OK, so I will attempt to boil down that second-to-last link into even plainer language, and talk about some of the implications. I'm coming at this from an evolutionary biology POV so what excites me is a bit different from what seems to be exciting everybody else about this discovery, but I will try to talk about both of the major reasons why this is interesting. Blasdelb and others, please correct me if I've gone astray. The great thing that these researchers have discovered is that there is a single gene which may in some ways demonstrate how the transition from prokaryotic to eukaryotic cells occurred, and which may also have wide-ranging applications for medicine and biotechnology.
As has been mentioned above, you can divide life up into two domains*: the Prokarya and the Eukarya. In the Eukarya, you have everything whose cells have nuclei and other membrane-bound organelles. This includes plants and animals and every other living thing you encounter that is visible with the naked eye, and lots of things you can't. What I mean by membrane-bound organelles is that the cells have little packets of functionality in them that serve a purpose analogous to the organs in a body and that are surrounded by a fatty membrane very similar to the one that encloses the cell itself. This is the signature evolutionary "invention" that allowed cells to become much more efficient and specialized and powerful and which was probably a necessary (if not sufficient) precondition for multicellular life to arise. It's a very big thing, in terms of evolutionary history, and the presence or absence of this trait basically divides all life in two.
A big unanswered question in cellular biology has been what actually caused that innovation to happen, and what did the precursors of eukaryotic cells look like. We know that the first cells were prokaryotes and that eukaryotes arose from them, but we don't have a great idea of how this might have happened. This research seems to represent a major advance in terms of giving us some idea of how that might have occured. The researchers were able to insert a single gene, the gene coding for the protein Caveolin, into some E. coli cells, which are prokaryotic. When they did this, the E. coli made vesicles (little bubbles of membrane) full of Caveolin that look a whole lot like very basic organelles! (They did it by basically making pits in their surfaces and then pinching off those pits until they detached and became bubbles.) This gives us the first (to my knowledge) living demonstration of a possible mechanism by which the first organelles might have been made.
It is especially interesting because they did it with only one gene, showing that the formation of primitive organelles may have been a simpler process than previously assumed. It opens up a lot of questions surrounding how this process could be controlled and how it could be modified to create real organelles. It's also very interesting because it has lots of potential applications. This could perhaps become a novel drug delivery system wherein chemicals attached to the Caveolin or to the surface of the cell get transported into cells by becoming enclosed in these vesicles. This would perhaps enable us to move all kinds of things into cells that previously would not have been allowed to cross the cell membrane, and may open up a wide new swath of potential treatments.
It's a really very cool discovery. It's a cool enough discovery, to me, that I'm sort of surprised that it wasn't published in Science or Nature. Perhaps later if the researchers discover more about this process and its implications and applications it will be, though of course Cell is a very prestigious journal in its own right, and a lot of microbiologists will definitely be reading about this soon. Not as many evolutionary biologists though, which is odd because to me this discovery may be just as important to evolutionary biology as cell biology. It's not certain of course -- this may yet turn out to be a dead-end path, a scientific cul-de-sac with no real attachment to evolutionary history and no useful applications -- but it seems pretty likely and it's certainly very interesting and exciting to read about.
*Actually the Archea are more closely related to the Eukarya than the Bacteria are, despite the fact that Archea and Bacteria are both prokaryotes. The division of life into Prokarya and Eukarya is phylogenetically inaccurate but that's beside the point for our purposes here.
posted by Scientist at 6:01 AM on October 18, 2012 [16 favorites]
As has been mentioned above, you can divide life up into two domains*: the Prokarya and the Eukarya. In the Eukarya, you have everything whose cells have nuclei and other membrane-bound organelles. This includes plants and animals and every other living thing you encounter that is visible with the naked eye, and lots of things you can't. What I mean by membrane-bound organelles is that the cells have little packets of functionality in them that serve a purpose analogous to the organs in a body and that are surrounded by a fatty membrane very similar to the one that encloses the cell itself. This is the signature evolutionary "invention" that allowed cells to become much more efficient and specialized and powerful and which was probably a necessary (if not sufficient) precondition for multicellular life to arise. It's a very big thing, in terms of evolutionary history, and the presence or absence of this trait basically divides all life in two.
A big unanswered question in cellular biology has been what actually caused that innovation to happen, and what did the precursors of eukaryotic cells look like. We know that the first cells were prokaryotes and that eukaryotes arose from them, but we don't have a great idea of how this might have happened. This research seems to represent a major advance in terms of giving us some idea of how that might have occured. The researchers were able to insert a single gene, the gene coding for the protein Caveolin, into some E. coli cells, which are prokaryotic. When they did this, the E. coli made vesicles (little bubbles of membrane) full of Caveolin that look a whole lot like very basic organelles! (They did it by basically making pits in their surfaces and then pinching off those pits until they detached and became bubbles.) This gives us the first (to my knowledge) living demonstration of a possible mechanism by which the first organelles might have been made.
It is especially interesting because they did it with only one gene, showing that the formation of primitive organelles may have been a simpler process than previously assumed. It opens up a lot of questions surrounding how this process could be controlled and how it could be modified to create real organelles. It's also very interesting because it has lots of potential applications. This could perhaps become a novel drug delivery system wherein chemicals attached to the Caveolin or to the surface of the cell get transported into cells by becoming enclosed in these vesicles. This would perhaps enable us to move all kinds of things into cells that previously would not have been allowed to cross the cell membrane, and may open up a wide new swath of potential treatments.
It's a really very cool discovery. It's a cool enough discovery, to me, that I'm sort of surprised that it wasn't published in Science or Nature. Perhaps later if the researchers discover more about this process and its implications and applications it will be, though of course Cell is a very prestigious journal in its own right, and a lot of microbiologists will definitely be reading about this soon. Not as many evolutionary biologists though, which is odd because to me this discovery may be just as important to evolutionary biology as cell biology. It's not certain of course -- this may yet turn out to be a dead-end path, a scientific cul-de-sac with no real attachment to evolutionary history and no useful applications -- but it seems pretty likely and it's certainly very interesting and exciting to read about.
*Actually the Archea are more closely related to the Eukarya than the Bacteria are, despite the fact that Archea and Bacteria are both prokaryotes. The division of life into Prokarya and Eukarya is phylogenetically inaccurate but that's beside the point for our purposes here.
posted by Scientist at 6:01 AM on October 18, 2012 [16 favorites]
Oh hey, I know some of these words.
posted by mhoye at 6:05 AM on October 18, 2012 [2 favorites]
posted by mhoye at 6:05 AM on October 18, 2012 [2 favorites]
There is a surprising amount of bullshit published in Science and Nature when you know what to look for, and a lot of arbitrariness to how their papers are editorially selected and particularly how they are reviewed. Hardcore top journals like Cell tend to have lower smoke up the ass to fire ratios in general if only because they are reviewed by three people who are actually in the field, which selects strongly against bullshit, rather than one person in the field and two in others, which in theory would select against unremarkable research. I suspect that this is another example of that selecting against remarkable research as well.
posted by Blasdelb at 6:51 AM on October 18, 2012 [3 favorites]
posted by Blasdelb at 6:51 AM on October 18, 2012 [3 favorites]
Scientist: flagged as excellent.
posted by Fat Charlie the Archangel at 8:11 AM on October 18, 2012
posted by Fat Charlie the Archangel at 8:11 AM on October 18, 2012
tangentially related to this topic: how come we don't have nanomachines and designer bacteria yet?
posted by rebent at 8:48 AM on October 18, 2012
posted by rebent at 8:48 AM on October 18, 2012
I think it's pretty safe to say that if you expect it, it isn't much of an emergent property.
I guess what I'm saying is that there are all kinds of fascinating things out there that we would be totally blown away by if someone did it in a lab, but since that's just how it is in nature we never seem to fully appreciate the elegance of it.
posted by Kid Charlemagne at 8:50 AM on October 18, 2012 [1 favorite]
I guess what I'm saying is that there are all kinds of fascinating things out there that we would be totally blown away by if someone did it in a lab, but since that's just how it is in nature we never seem to fully appreciate the elegance of it.
posted by Kid Charlemagne at 8:50 AM on October 18, 2012 [1 favorite]
> rebent: how come we don't have nanomachines and designer bacteria yet?
Because we have no idea how to make them. This post is about a bunch of people at the forefront of the fields responsible for describing how to design bacteria getting jump-up-and-down excited because they discovered a plausible mechanism for (to draw a dumb construction analogy) how one might build a stone arch, when what you want is a kilometer-span tension bridge.
posted by Fraxas at 9:01 AM on October 18, 2012 [2 favorites]
Because we have no idea how to make them. This post is about a bunch of people at the forefront of the fields responsible for describing how to design bacteria getting jump-up-and-down excited because they discovered a plausible mechanism for (to draw a dumb construction analogy) how one might build a stone arch, when what you want is a kilometer-span tension bridge.
posted by Fraxas at 9:01 AM on October 18, 2012 [2 favorites]
well ok. not a stone arch. more like a 5-story brick building.
posted by Fraxas at 9:02 AM on October 18, 2012
posted by Fraxas at 9:02 AM on October 18, 2012
As the blogger for Small Things Considered, I thank all for the interesting and valuable comments. Although the blog has a lot of visitors, we don't get all that many comments, so this is much appreciated.
Let me response to some of the comments:
Blasdelb: First, let me thank you for calling the attention of Metafilterites to the article and for your kind words. I greatly enjoyed your comments on the comments. I found them superbly enlightening.
MartinWisse: Although the stated purpose of our blog is to tell good stories of interest to anyone who cares about the world of microbes, we write for readers who have had a college level-biology.
Scientist: I share your astonishment.
Various: I suppose that every astounding new finding reveals some emergent property. Why does that make the finding any less exciting?
posted by mschaechter at 9:53 AM on October 18, 2012 [4 favorites]
Let me response to some of the comments:
Blasdelb: First, let me thank you for calling the attention of Metafilterites to the article and for your kind words. I greatly enjoyed your comments on the comments. I found them superbly enlightening.
MartinWisse: Although the stated purpose of our blog is to tell good stories of interest to anyone who cares about the world of microbes, we write for readers who have had a college level-biology.
Scientist: I share your astonishment.
Various: I suppose that every astounding new finding reveals some emergent property. Why does that make the finding any less exciting?
posted by mschaechter at 9:53 AM on October 18, 2012 [4 favorites]
Kid Charlemagne: I'm no biochemist or molecular biologist, but what has fascinated me is how crazy insane complicated and rube-goldberg-esque the shit that goes on inside of cells is. It's incredible that it does what it does, but it's also incredible that it works at all. It's a testament to the power of evolution through natural selection, both in that it is capable of creating absolutely incredible results that are lightyears beyond our wildest imaginings to be able to recreate synthetically, but also in that the results that it creates don't have to make a lick of sense to a human, they just have to work.
There is just so much counterintuitive shit going on in there, so many molecules pulling double- or triple-duty, so many little switches and chaperones that need to be in place, so many multipartite globular proteins that have to be assembled from the outputs of a half a dozen genes that don't even reside anywhere near each other in the genome, it makes my head spin thinking about it. There's a sense that it's both way more complex than it seems like it ought to be, but also that if it were any simpler it just wouldn't work at all.
That is one of the reasons why I don't want to be a molecular biologist, actually. (I dabbled in it briefly.) I prefer the graceful elegance of ecology to the mad tangle of molecular biology. Ecological interactions make sense to me, even if they are often surprising and wonderful in their unexpectedness. Molecular interactions are just a jumble of stuck-together, jerry-rigged parts that just happened to be lying around, as far as I can tell.
posted by Scientist at 10:01 AM on October 18, 2012
There is just so much counterintuitive shit going on in there, so many molecules pulling double- or triple-duty, so many little switches and chaperones that need to be in place, so many multipartite globular proteins that have to be assembled from the outputs of a half a dozen genes that don't even reside anywhere near each other in the genome, it makes my head spin thinking about it. There's a sense that it's both way more complex than it seems like it ought to be, but also that if it were any simpler it just wouldn't work at all.
That is one of the reasons why I don't want to be a molecular biologist, actually. (I dabbled in it briefly.) I prefer the graceful elegance of ecology to the mad tangle of molecular biology. Ecological interactions make sense to me, even if they are often surprising and wonderful in their unexpectedness. Molecular interactions are just a jumble of stuck-together, jerry-rigged parts that just happened to be lying around, as far as I can tell.
posted by Scientist at 10:01 AM on October 18, 2012
Welcome to MeFi, mschaechter. You might want to re-set your Homepage URL to point to the Small Things site; right now it just goes to Google.
(To do so, click on your name next to the "welcome back:" at the top of the page. Then click on "edit profile". Scroll down to "Homepage URL", paste it there, and finally "Save your Preferences".)
posted by benito.strauss at 11:13 AM on October 18, 2012
(To do so, click on your name next to the "welcome back:" at the top of the page. Then click on "edit profile". Scroll down to "Homepage URL", paste it there, and finally "Save your Preferences".)
posted by benito.strauss at 11:13 AM on October 18, 2012
Welcome to MetaFilter, mschaechter!
"As the blogger for Small Things Considered, I thank all for the interesting and valuable comments. Although the blog has a lot of visitors, we don't get all that many comments, so this is much appreciated."
I've been following your blog religiously since it started, but knowing that you particularly appreciate comments I'll be sure to start writing in some.
posted by Blasdelb at 11:32 AM on October 18, 2012
"As the blogger for Small Things Considered, I thank all for the interesting and valuable comments. Although the blog has a lot of visitors, we don't get all that many comments, so this is much appreciated."
I've been following your blog religiously since it started, but knowing that you particularly appreciate comments I'll be sure to start writing in some.
posted by Blasdelb at 11:32 AM on October 18, 2012
Darn you Blasdelb, I just barely got through that last fantastic post!
My first college biology course was in 1973. Retook biology 20 years later, along with microbiology. Nearly 20 years have passed. Reading your posts is like wading through honey--slow going, but sooo delicious.
...what has fascinated me is how crazy insane complicated and rube-goldberg-esque the shit that goes on inside of cells is. It's incredible that it does what it does, but it's also incredible that it works at all.
And the deeper you go, the weirder it gets!
posted by BlueHorse at 8:48 PM on October 18, 2012 [1 favorite]
My first college biology course was in 1973. Retook biology 20 years later, along with microbiology. Nearly 20 years have passed. Reading your posts is like wading through honey--slow going, but sooo delicious.
...what has fascinated me is how crazy insane complicated and rube-goldberg-esque the shit that goes on inside of cells is. It's incredible that it does what it does, but it's also incredible that it works at all.
And the deeper you go, the weirder it gets!
posted by BlueHorse at 8:48 PM on October 18, 2012 [1 favorite]
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posted by MartinWisse at 3:18 AM on October 18, 2012 [2 favorites]