This has been known for a while, but perhaps not broadly known, and not by "the general public". The link to the ICLAC in TFS is evidence of that.
The actual paper will answer your questions, but briefly: people make mistakes in maintaining cell lines, and contamination is easier than you think, particularly in primary cell lines.
I didn't see the authors mention if reproducibility sorts this out, if someone can't reproduce the results in another cell line or in an animal model, the original results are considered context dependent.
The FDA Advisory Committee materials and presentations are here, for those interested.
Note that this is for a very specific genetic cause of blindness, where a mutation in a gene for an enzyme results in effective loss of that specific enzyme. The drug is a retroviral vector encoding only the missing gene. Other causes of blindness, genetic or otherwise, wouldn't benefit from this treatment.
Pretty amazing, and a long time coming for gene therapy, since Jesse Gelsinger's death prompted a long close look at using adenoviral vectors for gene therapy.
...you have to break a few eggs. A few lives lost every year due to "terrists" are a small price to pay for freedom.
I am willing to risk the ridiculously small chance that my family and I will die in a terrorist incident in order to preserve our freedoms, despite continued government attempts to erode them (Patriot Act, etc.). I'd like to think that anyone sufficiently educated in mathematics and history would logically come to a similar conclusion.
It isn't incumbent upon Google or Facebook to separate fact from fiction, never mind deal in shades of grey. It isn't their job to think for us, and anyone who thinks so, clearly isn't thinking.;)
While I admit that I do not work in the real estate industry, I've never heard of a bank loaning enough to cover an extra $782,000 over asking price with a 10% or even 20% down payment. Banks want to see a safety margin between how much they loan and the value of a house. If the house is worth the asking price of $1,688,000, and a buyer puts down 20% and then defaults, the bank could quickly sell the house for 10% under the value and still make a profit. It's when they have to sell for less than the remaining value of the mortgage that they lose money, and they don't want to be in that position.
So if someone is buying a $1.68M house for $2.47M, if they aren't buying with cash, they are putting down >$1M for sure. So while maybe not enough for retirement, it's certainly a good portion of the way there.
FDA doesn't issue press releases about the status of drug applications (NDAs). Those are under confidentiality agreements due to trade secrets, etc. However, the NDA sponsor can release any information they want about their application.
So, yes, it could be hype. But I would bet any investors/donors want to see evidence that it is truly fast tracked, and could sue for fraud if not.
This guy has what it takes to be a future banking exec, pharma exec, or a US senator. He'd better immigrate now, before the US builds a wall on its border with the UK.
This is also true for the aurora borealis (northern lights). People report hearing sounds when watching them, but you can analyze the audio from video recordings and see that there is no sound. Or record audio only during an aurora borealis and play it back later: nothing.
While it might be 20 years, with the possibility of additional exclusivity, the clock starts when the patent is filed, not when the drug is approved and available for sale. It can take 10 years for a drug to make it to market after that clock starts ticking. Pharma companies have become more efficient at getting drugs to market and extending that exclusivity period, but it rarely lasts more than 12 years. That's part of the reason that there is a shift towards manufacturers developing biologics: the regulatory landscape in the US only just began allowing for biosimilars and the barrier to entry is very high. Barrier to entry for a generic small molecule is very low.
As for how well the system functions, we only need look at countries with single payer systems to understand what is wrong with pharmaceutical pricing in the US. The US govt is not allowed to negotiate prices with drug manufacturers. Medicare and Medicaid can choose not to cover a drug, but they can't be involved in setting the price. Contrast that with Germany, where there is a formula to determine the price of a new drug based on how much more efficacious and safe it is than the standard of care (not placebo). Not better than drug X? Then it can't cost more than drug X, possibly less, if it is even approved.
Absolutely not unimaginable, which is why it is so cool. I see two really hard problems to solve on that path: 1) getting cells to differentiate into the appropriate cell types in the right place; 2) getting the vasculature correct.
#1 is hard when starting with a scaffold, where everything is adult-sized from the start and has to be organized at the end. Maybe we'll need breakthroughs in understanding regeneration in animals capable of it (e.g., newts) and how they regrow adult-sized structures, rather than embryonic-sized structures that scale up. It seems like it would be easier to follow the route of growing from an embryonic size, maybe starting with an embryoid body (clump of stem cells, not too different from a fertilized egg after a few divisions) and directing the growth.
#2 is hard for growing any organ in a vat, and is part of #1, but really important because without appropriate vasculature the organ will die. Obviously, there are more important reasons why this needs to be correct for a lab grown heart (can't pump blood, it's main purpose, without proper vasculature). The researchers in TFA found that the stem cells followed the scaffolding of the vasculature closely. That's good, but they didn't become vasculature cells, just cardiac muscle cells. Plus, if the original heart had narrowed blood vessels due to atherosclerosis/plaque, the final vessels formed by the stem cells were also narrow. Furthermore, the microvasculature (the very tiny blood vessels) were closed off or clogged by stem cells, so nutrient distribution to those cells was incomplete and (if I recall) many died in the deep tissue.
Your analogy is not exactly correct. Think of it as removing the bricks from a building and leaving all of the mortar in place. You then put new bricks into the mortar scaffolding where the old ones were. Oddly, you mention soap, which is sort of what is used to lyse (dissolve) the cells and not affect the matrix. They have photographs and present other data of the scaffolding (ECM), as well as test it to make sure it isn't altered. This is far from the first time this technique to remove cells from a matrix has been used. But it isn't a fast process either. I believe they mention it takes ~400 hours.
What's new is that instead of having cells in a dish that "beat", they have cells approximating the size and shape of a left ventricle or cross-sections of a human heart and are exhibiting correct functional behavior (although not quite at the level of performance of a normal heart). This is arguably one of the first major steps in going from patient's skin cells -> stem cells -> cardiac cells in a dish -> cardiac cells in the shape of a heart -> lab grown heart. (Probably a step or two downplayed in there.)
The summary is somewhat inaccurate and oversimplified (this is Slashdot, of course).
The authors took donor hearts and removed all the cardiac cells, leaving only the extracellular matrix, which is the scaffolding that cells reside in. They then created stem cells from skin cells, not via a technique called "messenger RNA" (which is a type of biological molecule and not a technique), but by reprogramming the skin cells by providing synthetic messenger RNAs that instruct the cells to make 5 proteins that cause a "reversal" to a stem cell-like state. These new stem cells were instructed to become cardiac cells, which spontaneously exhibited "a heart beat", and then seeded onto slices of the cardiac matrix from a donor heart, and even a full heart. The cells contracted in unison, and could be "paced" by a "pacemaker".
Limitations of this approach are that the you need a human heart to start with (until a scaffold could be 3D printed, for example), cells did not fully differentiate into mature heart muscle cells, don't seem to maintain this fate past a certain time frame, didn't develop into all cell types needed for a functioning heart, and contracted with only a fraction of the force that a normal human heart does. But damn, the bioreactor with "grown" heart is incredible to behold (figure 6E), and this appears to be an interesting step forward to lab grown organs.
- for this to go horribly wrong in an entertaining science fiction kind of way. "We left him in too long and he reverted to a mass of stem cells."
Basically. Although, you'd have to find a way to provide doxycycline (the drug that activates the genes in question) to all of their cells once the person couldn't drink. Submerging them in a vat of fluid, Matrix style.
From TFA:
Continuous induction of OSKM in 4F mice by administration of doxycycline in drinking water resulted in significant weight loss and high mortality after 4 days (Figures 3 A and 3B). This likely resulted from the dedifferentiation of cells in vital organs and subsequent loss of organ function.
If you wanted to take it farther, you could use all of those stem cells to create clones of the original. Do dedifferentiated neurons lose memories? The connections will likely disappear, and the answer is probably "yes", but one could have fun with it in a story.
I am pretty sure it was posted on Slashdot (can't find it), but the Boston Globe reported in 2002 that scientists at MIT could convincingly alter video to make it appear that someone said something they didn't, with only 2 minutes of footage:
(Link to article on Boston Globe is dead.) They couldn't alter the audio convincingly, or at least didn't try. However, I also recall seeing on Slashdot (10+ years ago; also can't find it) that someone (Bell? MIT?) could take about 2,000 recorded words from an individual and create convincing audio of words and sentences not previously recorded.
Post-truth politics won't matter when someone releases convincingly altered video and audio of a public figure doing something that they never did.
Thanks. The authors state that their calculations estimate the number of galaxies in the universe to be 10x greater than estimated via observational data. I assume Gizmodo, the submitter, and the Slashdot editor all did not even read the abstract.
Any idea why the discrepancy? (How do you get from 10 to 20 other than fat finger? Am I missing something in the paper?)
Yes, there are private clinics in Canada, but it might be dependent upon the province. Typically it is something the wealthier people use, as they might also have private insurance to defray costs (and can by definition afford to pay more for treatment). So if you can afford it, and don't want to wait, you go to a private clinic or doctor. Otherwise you try to find the one with the shortest wait time.
I've tried various search engines, and whenever I used Bing, it would return results that it thinks I want, but not actually what I want. For that reason alone, I can't recommend it for anyone competent.
Your response doesn't exactly address the concern: are these changes heritable?
There is evidence to suggest that they are transmitted to offspring, maternally and possibly paternally:
http://www.ncbi.nlm.nih.gov/pm... "These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood."
http://www.ncbi.nlm.nih.gov/pu... "Here we assessed whether these infant [DNA methylation (DNAm)] patterns are detectable in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status.... Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children... These DNAm changes appear to be tobacco-specific."
http://www.ncbi.nlm.nih.gov/pm... "Paternal smoking and germ cell death: a mechanistic link to the effects of cigarette smoke on spermatogenesis and possible long-term sequelae in offspring"
It's not clear at this time whether they are transmitted to the third generation.
You raise an interesting point. Most drugs used to treat psychiatric conditions have a narrow therapeutic window: if the dose is too low the treatment is not effective; if the dose is too high then adverse events result. That's why many psychiatric drugs come in a variety of doses and physicians titrate the dose for new patients. On the other hand, most drugs to treat other medical conditions have a wider therapeutic window: it's OK if the dose isn't perfectly accurate.
Interestingly, it appears that epinephrine for the treatment of anaphylaxis has a narrow therapeutic window, and too little, too much, or injecting improperly can result in death:
As it relates to your question ("can a suicidal person administer the proper dose?"), can a person dying of anaphylaxis measure an accurate dose and properly inject?
Why would we pass up a chance to learn? Scientists from all branches of science learn by tinkering, and this would be another form, even if we only did it to validate our understanding (once sufficiently advanced) of how DNA sequences yield a very specific body pattern and size and set of behaviors.
Besides, most people forget that the environment the dinosaurs lived in was very different from ours, both in temperature/climate and air composition, making it a much more difficult problem than "can we clone them?". For example, prehistoric insects were very large, larger than what the current oxygen levels in our atmosphere could support since they don't have lungs and breathe basically via diffusion. So, for specific values of "prehistoric" the difficulties involve artificial environments.
Slashdot Mirror
This has been known for a while, but perhaps not broadly known, and not by "the general public". The link to the ICLAC in TFS is evidence of that.
The actual paper will answer your questions, but briefly: people make mistakes in maintaining cell lines, and contamination is easier than you think, particularly in primary cell lines.
I didn't see the authors mention if reproducibility sorts this out, if someone can't reproduce the results in another cell line or in an animal model, the original results are considered context dependent.
Really? This is the biggest problem of the patent system, requiring an immediate legislative fix?
The FDA Advisory Committee materials and presentations are here, for those interested.
Note that this is for a very specific genetic cause of blindness, where a mutation in a gene for an enzyme results in effective loss of that specific enzyme. The drug is a retroviral vector encoding only the missing gene. Other causes of blindness, genetic or otherwise, wouldn't benefit from this treatment.
Pretty amazing, and a long time coming for gene therapy, since Jesse Gelsinger's death prompted a long close look at using adenoviral vectors for gene therapy.
...you have to break a few eggs. A few lives lost every year due to "terrists" are a small price to pay for freedom.
I am willing to risk the ridiculously small chance that my family and I will die in a terrorist incident in order to preserve our freedoms, despite continued government attempts to erode them (Patriot Act, etc.). I'd like to think that anyone sufficiently educated in mathematics and history would logically come to a similar conclusion.
It isn't incumbent upon Google or Facebook to separate fact from fiction, never mind deal in shades of grey. It isn't their job to think for us, and anyone who thinks so, clearly isn't thinking. ;)
Thinking about possible means of failure reminds me of Heinlein's The Roads Must Roll. Can't forget politics as a possible failure point.
Assuming they paid cash for the house.
While I admit that I do not work in the real estate industry, I've never heard of a bank loaning enough to cover an extra $782,000 over asking price with a 10% or even 20% down payment. Banks want to see a safety margin between how much they loan and the value of a house. If the house is worth the asking price of $1,688,000, and a buyer puts down 20% and then defaults, the bank could quickly sell the house for 10% under the value and still make a profit. It's when they have to sell for less than the remaining value of the mortgage that they lose money, and they don't want to be in that position.
So if someone is buying a $1.68M house for $2.47M, if they aren't buying with cash, they are putting down >$1M for sure. So while maybe not enough for retirement, it's certainly a good portion of the way there.
FDA doesn't issue press releases about the status of drug applications (NDAs). Those are under confidentiality agreements due to trade secrets, etc. However, the NDA sponsor can release any information they want about their application.
So, yes, it could be hype. But I would bet any investors/donors want to see evidence that it is truly fast tracked, and could sue for fraud if not.
This guy has what it takes to be a future banking exec, pharma exec, or a US senator. He'd better immigrate now, before the US builds a wall on its border with the UK.
This is also true for the aurora borealis (northern lights). People report hearing sounds when watching them, but you can analyze the audio from video recordings and see that there is no sound. Or record audio only during an aurora borealis and play it back later: nothing.
the name Wesley might "taste" like boiled cabbage
I am pretty sure the name Wesley tastes like a nice MLT, where the mutton is nice and lean.
Or perhaps it tastes like iocaine powder if you are a Sicilian.
While it might be 20 years, with the possibility of additional exclusivity, the clock starts when the patent is filed, not when the drug is approved and available for sale. It can take 10 years for a drug to make it to market after that clock starts ticking. Pharma companies have become more efficient at getting drugs to market and extending that exclusivity period, but it rarely lasts more than 12 years. That's part of the reason that there is a shift towards manufacturers developing biologics: the regulatory landscape in the US only just began allowing for biosimilars and the barrier to entry is very high. Barrier to entry for a generic small molecule is very low.
As for how well the system functions, we only need look at countries with single payer systems to understand what is wrong with pharmaceutical pricing in the US. The US govt is not allowed to negotiate prices with drug manufacturers. Medicare and Medicaid can choose not to cover a drug, but they can't be involved in setting the price. Contrast that with Germany, where there is a formula to determine the price of a new drug based on how much more efficacious and safe it is than the standard of care (not placebo). Not better than drug X? Then it can't cost more than drug X, possibly less, if it is even approved.
Absolutely not unimaginable, which is why it is so cool. I see two really hard problems to solve on that path: 1) getting cells to differentiate into the appropriate cell types in the right place; 2) getting the vasculature correct.
#1 is hard when starting with a scaffold, where everything is adult-sized from the start and has to be organized at the end. Maybe we'll need breakthroughs in understanding regeneration in animals capable of it (e.g., newts) and how they regrow adult-sized structures, rather than embryonic-sized structures that scale up. It seems like it would be easier to follow the route of growing from an embryonic size, maybe starting with an embryoid body (clump of stem cells, not too different from a fertilized egg after a few divisions) and directing the growth.
#2 is hard for growing any organ in a vat, and is part of #1, but really important because without appropriate vasculature the organ will die. Obviously, there are more important reasons why this needs to be correct for a lab grown heart (can't pump blood, it's main purpose, without proper vasculature). The researchers in TFA found that the stem cells followed the scaffolding of the vasculature closely. That's good, but they didn't become vasculature cells, just cardiac muscle cells. Plus, if the original heart had narrowed blood vessels due to atherosclerosis/plaque, the final vessels formed by the stem cells were also narrow. Furthermore, the microvasculature (the very tiny blood vessels) were closed off or clogged by stem cells, so nutrient distribution to those cells was incomplete and (if I recall) many died in the deep tissue.
Your analogy is not exactly correct. Think of it as removing the bricks from a building and leaving all of the mortar in place. You then put new bricks into the mortar scaffolding where the old ones were. Oddly, you mention soap, which is sort of what is used to lyse (dissolve) the cells and not affect the matrix. They have photographs and present other data of the scaffolding (ECM), as well as test it to make sure it isn't altered. This is far from the first time this technique to remove cells from a matrix has been used. But it isn't a fast process either. I believe they mention it takes ~400 hours.
What's new is that instead of having cells in a dish that "beat", they have cells approximating the size and shape of a left ventricle or cross-sections of a human heart and are exhibiting correct functional behavior (although not quite at the level of performance of a normal heart). This is arguably one of the first major steps in going from patient's skin cells -> stem cells -> cardiac cells in a dish -> cardiac cells in the shape of a heart -> lab grown heart. (Probably a step or two downplayed in there.)
(understand the fucking article)
The summary is somewhat inaccurate and oversimplified (this is Slashdot, of course).
The authors took donor hearts and removed all the cardiac cells, leaving only the extracellular matrix, which is the scaffolding that cells reside in. They then created stem cells from skin cells, not via a technique called "messenger RNA" (which is a type of biological molecule and not a technique), but by reprogramming the skin cells by providing synthetic messenger RNAs that instruct the cells to make 5 proteins that cause a "reversal" to a stem cell-like state. These new stem cells were instructed to become cardiac cells, which spontaneously exhibited "a heart beat", and then seeded onto slices of the cardiac matrix from a donor heart, and even a full heart. The cells contracted in unison, and could be "paced" by a "pacemaker".
Limitations of this approach are that the you need a human heart to start with (until a scaffold could be 3D printed, for example), cells did not fully differentiate into mature heart muscle cells, don't seem to maintain this fate past a certain time frame, didn't develop into all cell types needed for a functioning heart, and contracted with only a fraction of the force that a normal human heart does. But damn, the bioreactor with "grown" heart is incredible to behold (figure 6E), and this appears to be an interesting step forward to lab grown organs.
- for this to go horribly wrong in an entertaining science fiction kind of way. "We left him in too long and he reverted to a mass of stem cells."
Basically. Although, you'd have to find a way to provide doxycycline (the drug that activates the genes in question) to all of their cells once the person couldn't drink. Submerging them in a vat of fluid, Matrix style.
From TFA:
Continuous induction of OSKM in 4F mice by administration of doxycycline in drinking water resulted in significant weight loss and high mortality after 4 days (Figures 3 A and 3B). This likely resulted from the dedifferentiation of cells in vital organs and subsequent loss of organ function.
If you wanted to take it farther, you could use all of those stem cells to create clones of the original. Do dedifferentiated neurons lose memories? The connections will likely disappear, and the answer is probably "yes", but one could have fun with it in a story.
I am pretty sure it was posted on Slashdot (can't find it), but the Boston Globe reported in 2002 that scientists at MIT could convincingly alter video to make it appear that someone said something they didn't, with only 2 minutes of footage:
http://www.rense.com/general25...
(Link to article on Boston Globe is dead.) They couldn't alter the audio convincingly, or at least didn't try. However, I also recall seeing on Slashdot (10+ years ago; also can't find it) that someone (Bell? MIT?) could take about 2,000 recorded words from an individual and create convincing audio of words and sentences not previously recorded.
Post-truth politics won't matter when someone releases convincingly altered video and audio of a public figure doing something that they never did.
"emcmullin" as in "Evan McMullin" from Utah?
This is brilliant.
Thanks. The authors state that their calculations estimate the number of galaxies in the universe to be 10x greater than estimated via observational data. I assume Gizmodo, the submitter, and the Slashdot editor all did not even read the abstract.
Any idea why the discrepancy? (How do you get from 10 to 20 other than fat finger? Am I missing something in the paper?)
Yes, there are private clinics in Canada, but it might be dependent upon the province. Typically it is something the wealthier people use, as they might also have private insurance to defray costs (and can by definition afford to pay more for treatment). So if you can afford it, and don't want to wait, you go to a private clinic or doctor. Otherwise you try to find the one with the shortest wait time.
Agreed, and then some.
I've tried various search engines, and whenever I used Bing, it would return results that it thinks I want, but not actually what I want. For that reason alone, I can't recommend it for anyone competent.
Your response doesn't exactly address the concern: are these changes heritable?
There is evidence to suggest that they are transmitted to offspring, maternally and possibly paternally:
http://www.ncbi.nlm.nih.gov/pm...
"These data suggest that prenatal exposure to tobacco smoke is associated with reproducible epigenetic changes that persist well into childhood."
http://www.ncbi.nlm.nih.gov/pu... ... Striking concordance was found between the pattern of prenatal smoking associated DNAm among preschool aged children... These DNAm changes appear to be tobacco-specific."
"Here we assessed whether these infant [DNA methylation (DNAm)] patterns are detectable in early childhood, whether they are specific to smoking, and whether childhood DNAm can classify prenatal smoke exposure status.
Pay-walled review of the literature from Feb 2016:
http://www.ncbi.nlm.nih.gov/pu...
http://www.ncbi.nlm.nih.gov/pm...
"Paternal smoking and germ cell death: a mechanistic link to the effects of cigarette smoke on spermatogenesis and possible long-term sequelae in offspring"
It's not clear at this time whether they are transmitted to the third generation.
You raise an interesting point. Most drugs used to treat psychiatric conditions have a narrow therapeutic window: if the dose is too low the treatment is not effective; if the dose is too high then adverse events result. That's why many psychiatric drugs come in a variety of doses and physicians titrate the dose for new patients. On the other hand, most drugs to treat other medical conditions have a wider therapeutic window: it's OK if the dose isn't perfectly accurate.
Interestingly, it appears that epinephrine for the treatment of anaphylaxis has a narrow therapeutic window, and too little, too much, or injecting improperly can result in death:
http://www.ncbi.nlm.nih.gov/pu...
http://www.ncbi.nlm.nih.gov/pu...
As it relates to your question ("can a suicidal person administer the proper dose?"), can a person dying of anaphylaxis measure an accurate dose and properly inject?
Why would we pass up a chance to learn? Scientists from all branches of science learn by tinkering, and this would be another form, even if we only did it to validate our understanding (once sufficiently advanced) of how DNA sequences yield a very specific body pattern and size and set of behaviors.
Besides, most people forget that the environment the dinosaurs lived in was very different from ours, both in temperature/climate and air composition, making it a much more difficult problem than "can we clone them?". For example, prehistoric insects were very large, larger than what the current oxygen levels in our atmosphere could support since they don't have lungs and breathe basically via diffusion. So, for specific values of "prehistoric" the difficulties involve artificial environments.