I disagree with a lot of the parent's post, but this part is reasonably solved. When you decellularize an ECM, the vessel walls remain intact. Then you reseed with HUVECs (an endothelial cell line), and they tend to find their way back onto the old vessel walls to form a vasculature.
But you are absolutely right that the microarchitecture of the tissue is very, very significant to proper function.
While the ECM molecular components are conserved as you point out in another post, their distribution (e.g., how much collagen IV, matrix-embedded glycoproteins, etc.), stiffness, and microarchitecture vary quite a bit from species to species, organ to organ, and even individual to individual. And this radically affects the phenotype of the cells that you transplant on them. Both cancer and "normal" epithelial cells are known to change their motility, proliferation, and even polarization characteristics based upon the stiffness of the tissue, for example.
And take a look at livers: pig livers have a very thick membrane between hepatic lobules, making them great for textbooks, as you can very clearly see portal triads and central veins and the overall lobular outlines. Human tissue, by contrast, has very thin membranes between lobules that can scarcely be seen in H&E pathology. This makes pig liver ECM a very poor starting point for growing a human organ replacement. When our collaborators build bioengineered liver tissue, they actually start with decellularized ferret livers because their structures are closer to humans than pigs.
This is why a mix of 3-D printing and seeding progenitor cells could be promising in the future. If you could 3-D print the ECM to have the correct spatial distribution and mechanical properties, you'd have a much better starting point when you seed them with progenitor cells to grow the epithelium / parenchyme, HUVECs to grow the vessels, etc.
Aside: I have yet to see XCM in 10+ years of cancer research and tissue biomechanics work. It's ECM.
Wolfram announced his latest idea - that there needed to be some kind of pliable material available next to toilets with which to clean one's bum. This material, he said, is going to be really soft, probably a couple of layers thick, and needed to be on some kind of continuous dispenser mechanism which he is developing.
I figure there needs to be something similar to the
National Vaccine Injury Compensation Program: here, something that makes society safer overall (vaccines) is promoted by reducing the risk of an individual harm (a rare side effect). This says: "Pay in and help make society safer, and if it individually harms you, we've got your back."
So, why not something for driverless cars? You opt into a driverless car with the societal benefit of reduced accidents, and if your driverless car harms you individually (physically or legally), the national defense fund takes over.
this and this are pretty similar. I see this most frequently in multi-person text messages from iPhone, and indeed, in the default txt message client, these often appear as attachments / multimedia instead of text.
Good point. Since I've seen this issue sporadically with multiple iPhones sending messages to Android, I had figured it was more on the iPhone end with a standards-breaking or standards-bending SMS behavior.
BitZtream (692029) wrote:
That doesn't happen on iPhones, perhaps its your end thats the problem.
theurge14 (820596) wrote:
Sounds like it might be a problem on your phone. I haven't seen this problem at all on iPhones.
[snark]Of course the standards-breaking message sender renders its standards-breaking messages correctly.[/snark]
More seriously, we have:
iPhone -> iPhone : no problem
non-iPhone -> iPhone : no problem
non-iPhone -> Android : no problem
iPhone -> Android : textual messages appearing like multimedia attachments
This suggests that iPhone is using iChat or similar to "txt" with other phones and encoding outgoing info in some sort of multimedia or attachment tags within the SMS format.
I can't stress enough how much it drives me up the wall to get text messages on my Android phone from iPhones. Far too often, they show as "multimedia" messages requiring a data connection just to download 5-7 words of text.
Or when an iPhone user sends a txt message to several people, and each "reply to all" response appears as a separate, disjoint SMS thread without the full conversation or context.
Personally, as a guy with hearing loss that's really cutting into those handy consonant sounds above 2000 Hz, I'm thrilled at the idea of real-time "closed captioning" placed under each speaker. Right now, noisy restaurants and lectures can be a bit of a nightmare, even with top-of-the-line hearing aids.
Many thanks from another member of the cancer community. So glad this has shown such tremendous results for you. Hope we can some day understand this better and help more people! All the best wishes for continued health! -- Paul
I am not a biologist so forgive me my ignorance but when people say that DNA is the blueprint for an organism I never understand how a bunch of proteins can determine an organism's shape and behavior. Aren't there more factors that determine those things, like the surroundings in which the DNA is used, like chemicals that the growing organism is surrounded with, temperature, etc?
You're absolutely right. Microenvironment -- the cell's chemical, mechanical, and physical environment, determines which genes are switched on, whether those proteins get made, and how and whether they interact with other proteins to alter cell behavior.
This has been a challenge (and perhaps even a failure) of many current genome projects, which are often reductionist to the point of ignoring much of these features, whereas "context" may well be more important than the genome.
There was a big splashy paper in the New England Journal of Medicine last year, where multiple regions of a single tumor were sequenced. It was found that while there were significant differences in the genome across a single tumor, the cell phenotypes (their behavior) was much more convergent. That is, even with significantly different genes, these cells found a way to function similarly when presented a similar environmental context.
My cancer research website is down, too. (Only works on computers that had cached the DNS entries.) So much for inviting seminar speakers today.
I'm an academic. I set my site up years ago (before all the SOPA business) and don't have time to muck with moving my site around, hosting DNS here and content there, and the like. I barely have time to maintain content in the middle of a busy research career. I suppose I'm now supposed to be an expert on mathematical modeling + cancer + hosting my own DNS?
It's always worth keeping in mind that these things affect far more than business sites.
These models tend to be object-oriented in the sense that a genetics "module" interacts with a protein signaling module, etc. In each module, you'd have the member data (say, a list of all proteins) and member functions (say, a model of the reaction network that discretizes the massive system of ODEs).
The objects then interact. You have well-defined interfaces between these modules to codify currently known (or hypothesized!) biology. For example, members of the proteins module activate certain genes in the genetics module to (eventually) drive synthesis of more proteins.
You write the rules based upon our current state-of-the-art in understanding cell biology, simulate, and see what happens. To the extent that it quantitatively matches experiments, we can assess the underlying hypotheses, refine them, or toss them out.
In this work, it looks like they pulled information from 900 papers on this species of bacterium to simulate 525 genes, God knows how many proteins (genes can encode multiple proteins), and 28 processes.
Notably, there is no spatial component (e.g., transport of proteins, RNAs, cell volume changes, cell mechanics, etc.), but it's an incredible set of work. And to be able to predict phenotype solely based upon the emergent behavior of this network is pretty incredible.
(replying to myself): Also, if her statistics are good, she might consider joining the biostatistics core at a med school or medical company. There will be no shortage of clinical trials or other biological experiments where they really need a statistician (or mathematician) to help with experimental design and statistical analysis / hypothesis testing.
If she has additional background in biology, or computing skills, she might find work in a computational biology lab as a staff scientist or assistant... but the real key is to have a complementary skill, where mathematics helps propel the analysis and work.
3d printers have a precision tolerance of something on the order of about eighty to a hundred microns, or often worse... particularly for non-commercial home 3d-printers.
Lego is manufactured to a precision of less than 2 microns.
...
For comparison, Megabloks is manufactured to a precision of approximately 10 microns.
That's absolutely incredible. For comparison, the typical oxygen penetration length in tissue (the diffusion length scale: sqrt( diffusion constant / uptake rate)) is on the scale of 3-D printer precision: 100 microns.
Human cells are on scale of Megabloks precision: 10-20 microns in diameter.
A human cell nucleus is on the order of 5-7 microns in diameter: still larger than the 2 micron Lego precision! 2 microns is on the same order as the size of bacteria!
If you want some more introductory reading on (cancer) biology, written by a mathematician for those inclined towards physical sciences, I have a few free pubs you can visit. (Including the oxygen diffusion limitations above.)
Re:So is there an alternative?
on
Of Mice and Cancer
·
· Score: 4, Interesting
This is part of the motivation for developing computational models of cancer. Code up the biological assumptions, calibrate to mouse data, validate to the mouse. If it works, then the biology and calibration protocols are probably fine. Re-calibrate to humans (with changes to geometry, tissue properties, cell parameters, etc.), run the models on clinical data (pathology, imaging, proteomics, etc.), and see how it does.
Now, actually doing this is the subject of tricky ongoing work by many many teams of people (see the work in the NCI Physical Sciences Oncology Network), but it's being driven by just the types of problems stated in this thread.
We've been testing various aspects of this on breast cancer and lymphoma, and the results are encouraging, ranging from explaining "tissue artifacts" in pathology (due to fast timescale biophysics) to predicting correlations between mammography and pathology (due in part to necrotic core biomechanics + oxygen diffusion limitations), to predicting DCIS excision volumes. (See stuff here and
a few movies.)
For docking stations and such. Plenty of us plop our laptop onto a docking station or a USB hub + monitor + speakers + keyboard + mouse anyway.
It beats the hell out of hauling an overpriced 10-pound beast to the same office desk every day, when you can just keep better equipment (with better ergonomics) neatly arranged and haul a lighter machine to/from work.
Slashdot Mirror
Didn't mean to harp on it, BTW. Happens to me more than I'd like, too! Best -- Paul
I disagree with a lot of the parent's post, but this part is reasonably solved. When you decellularize an ECM, the vessel walls remain intact. Then you reseed with HUVECs (an endothelial cell line), and they tend to find their way back onto the old vessel walls to form a vasculature.
But you are absolutely right that the microarchitecture of the tissue is very, very significant to proper function.
While the ECM molecular components are conserved as you point out in another post, their distribution (e.g., how much collagen IV, matrix-embedded glycoproteins, etc.), stiffness, and microarchitecture vary quite a bit from species to species, organ to organ, and even individual to individual. And this radically affects the phenotype of the cells that you transplant on them. Both cancer and "normal" epithelial cells are known to change their motility, proliferation, and even polarization characteristics based upon the stiffness of the tissue, for example.
And take a look at livers: pig livers have a very thick membrane between hepatic lobules, making them great for textbooks, as you can very clearly see portal triads and central veins and the overall lobular outlines. Human tissue, by contrast, has very thin membranes between lobules that can scarcely be seen in H&E pathology. This makes pig liver ECM a very poor starting point for growing a human organ replacement. When our collaborators build bioengineered liver tissue, they actually start with decellularized ferret livers because their structures are closer to humans than pigs.
This is why a mix of 3-D printing and seeding progenitor cells could be promising in the future. If you could 3-D print the ECM to have the correct spatial distribution and mechanical properties, you'd have a much better starting point when you seed them with progenitor cells to grow the epithelium / parenchyme, HUVECs to grow the vessels, etc.
Aside: I have yet to see XCM in 10+ years of cancer research and tissue biomechanics work. It's ECM.
And naturally, he'll call it Wolfram paper. :-)
I figure there needs to be something similar to the National Vaccine Injury Compensation Program: here, something that makes society safer overall (vaccines) is promoted by reducing the risk of an individual harm (a rare side effect). This says: "Pay in and help make society safer, and if it individually harms you, we've got your back."
So, why not something for driverless cars? You opt into a driverless car with the societal benefit of reduced accidents, and if your driverless car harms you individually (physically or legally), the national defense fund takes over.
Furthermore, the passenger might be helping with the navigation, answering those critical emails, etc ... to help the driver keep focused on the road.
this and this are pretty similar. I see this most frequently in multi-person text messages from iPhone, and indeed, in the default txt message client, these often appear as attachments / multimedia instead of text.
Good point. Since I've seen this issue sporadically with multiple iPhones sending messages to Android, I had figured it was more on the iPhone end with a standards-breaking or standards-bending SMS behavior.
[snark]Of course the standards-breaking message sender renders its standards-breaking messages correctly.[/snark]
More seriously, we have:
This suggests that iPhone is using iChat or similar to "txt" with other phones and encoding outgoing info in some sort of multimedia or attachment tags within the SMS format.
I can't stress enough how much it drives me up the wall to get text messages on my Android phone from iPhones. Far too often, they show as "multimedia" messages requiring a data connection just to download 5-7 words of text.
Or when an iPhone user sends a txt message to several people, and each "reply to all" response appears as a separate, disjoint SMS thread without the full conversation or context.
The "universal translator" idea had crossed my mind, too. ;-)
Personally, as a guy with hearing loss that's really cutting into those handy consonant sounds above 2000 Hz, I'm thrilled at the idea of real-time "closed captioning" placed under each speaker. Right now, noisy restaurants and lectures can be a bit of a nightmare, even with top-of-the-line hearing aids.
Great answer to this type of comment. :-)
Many thanks from another member of the cancer community. So glad this has shown such tremendous results for you. Hope we can some day understand this better and help more people! All the best wishes for continued health! -- Paul
You're absolutely right. Microenvironment -- the cell's chemical, mechanical, and physical environment, determines which genes are switched on, whether those proteins get made, and how and whether they interact with other proteins to alter cell behavior.
This has been a challenge (and perhaps even a failure) of many current genome projects, which are often reductionist to the point of ignoring much of these features, whereas "context" may well be more important than the genome.
There was a big splashy paper in the New England Journal of Medicine last year, where multiple regions of a single tumor were sequenced. It was found that while there were significant differences in the genome across a single tumor, the cell phenotypes (their behavior) was much more convergent. That is, even with significantly different genes, these cells found a way to function similarly when presented a similar environmental context.
It's affecting a lot more than commerce.
My cancer research website is down, too. (Only works on computers that had cached the DNS entries.) So much for inviting seminar speakers today.
I'm an academic. I set my site up years ago (before all the SOPA business) and don't have time to muck with moving my site around, hosting DNS here and content there, and the like. I barely have time to maintain content in the middle of a busy research career. I suppose I'm now supposed to be an expert on mathematical modeling + cancer + hosting my own DNS?
It's always worth keeping in mind that these things affect far more than business sites.
Simplified answer:
These models tend to be object-oriented in the sense that a genetics "module" interacts with a protein signaling module, etc. In each module, you'd have the member data (say, a list of all proteins) and member functions (say, a model of the reaction network that discretizes the massive system of ODEs).
The objects then interact. You have well-defined interfaces between these modules to codify currently known (or hypothesized!) biology. For example, members of the proteins module activate certain genes in the genetics module to (eventually) drive synthesis of more proteins.
You write the rules based upon our current state-of-the-art in understanding cell biology, simulate, and see what happens. To the extent that it quantitatively matches experiments, we can assess the underlying hypotheses, refine them, or toss them out.
In this work, it looks like they pulled information from 900 papers on this species of bacterium to simulate 525 genes, God knows how many proteins (genes can encode multiple proteins), and 28 processes.
Notably, there is no spatial component (e.g., transport of proteins, RNAs, cell volume changes, cell mechanics, etc.), but it's an incredible set of work. And to be able to predict phenotype solely based upon the emergent behavior of this network is pretty incredible.
(replying to myself): Also, if her statistics are good, she might consider joining the biostatistics core at a med school or medical company. There will be no shortage of clinical trials or other biological experiments where they really need a statistician (or mathematician) to help with experimental design and statistical analysis / hypothesis testing.
If she has additional background in biology, or computing skills, she might find work in a computational biology lab as a staff scientist or assistant ... but the real key is to have a complementary skill, where mathematics helps propel the analysis and work.
3d printers have a precision tolerance of something on the order of about eighty to a hundred microns, or often worse... particularly for non-commercial home 3d-printers.
Lego is manufactured to a precision of less than 2 microns.
...
For comparison, Megabloks is manufactured to a precision of approximately 10 microns.
That's absolutely incredible. For comparison, the typical oxygen penetration length in tissue (the diffusion length scale: sqrt( diffusion constant / uptake rate)) is on the scale of 3-D printer precision: 100 microns.
Human cells are on scale of Megabloks precision: 10-20 microns in diameter.
A human cell nucleus is on the order of 5-7 microns in diameter: still larger than the 2 micron Lego precision! 2 microns is on the same order as the size of bacteria!
If you want some more introductory reading on (cancer) biology, written by a mathematician for those inclined towards physical sciences, I have a few free pubs you can visit. (Including the oxygen diffusion limitations above.)
Biological Background from Cristini and Lowengrub (2010) and some some tutorials here.
How about Southern California Public Radio?
http://www.scpr.org/programs/patt-morrison/2012/02/14/22523/monsanto-lawsuit
Also, New York Times:
http://www.nytimes.com/2012/02/08/dining/a-suit-airs-debate-on-organic-vs-modified-crops.html
This is part of the motivation for developing computational models of cancer. Code up the biological assumptions, calibrate to mouse data, validate to the mouse. If it works, then the biology and calibration protocols are probably fine. Re-calibrate to humans (with changes to geometry, tissue properties, cell parameters, etc.), run the models on clinical data (pathology, imaging, proteomics, etc.), and see how it does.
Now, actually doing this is the subject of tricky ongoing work by many many teams of people (see the work in the NCI Physical Sciences Oncology Network), but it's being driven by just the types of problems stated in this thread.
We've been testing various aspects of this on breast cancer and lymphoma, and the results are encouraging, ranging from explaining "tissue artifacts" in pathology (due to fast timescale biophysics) to predicting correlations between mammography and pathology (due in part to necrotic core biomechanics + oxygen diffusion limitations), to predicting DCIS excision volumes. (See stuff here and a few movies.)
For docking stations and such. Plenty of us plop our laptop onto a docking station or a USB hub + monitor + speakers + keyboard + mouse anyway.
It beats the hell out of hauling an overpriced 10-pound beast to the same office desk every day, when you can just keep better equipment (with better ergonomics) neatly arranged and haul a lighter machine to/from work.
Wow, by this google search, that amounts to just over 10% of the entire US GDP. Glad somebody's been genuinely productive this year.
Don't put unleaded in a diesel.