The problem is that they did not plan realistically, $25K to replicate these kind of experiments by an external lab is not doable. They took the best case scenario (what would it cost for the people that already did it once and have all the details solved) and tried to apply it to the worst case scenario (do it again by different people, with different equipment, without lots of necessary information, etc.)
These kind of chimeras are not necessary for this kind of risky situation, experimental animals are right now routinely "humanized" by modifying their genome in order for them to express human proteins, this makes the humanized animals susceptible to some human diseases and theoretically facilitates the appearance of pathogens that can now infect humans (specially viruses). The new chimeras of this post are actually safer since their offspring would not carry any human traits so they can't be mass produced.
At the beginning it was all very fuzzy and cases very uncharacteristic for viruses of the same family, but the research that has been done in the last few months is admirable, it is now completely clear that, even if it was unexpected, Zika acts like its mild fever type of related virus in adults (like Dengue and Yellow Fever) but becomes much more like the neurocentric cousins of the family in embryos (like West Nile and Japanese Encephalitis). Anybody that is following the reports, even if only the titles, was expecting this conclusion from the CDC and WHO.
I mean, this has been studied for many examples in the past but this experimental design results put a lot more weigh on this theory. I could not find the original article so I don't know what they used as a control, but as long as they deleted also equivalent sequences of the genome (not ERVs) without observing the drop of immunity this approach would clearly demonstrate this mechanism.
I understood the paper differently, researchers used gut viruses to trick the mouse immune system to go into a "colonization resistance" state that prevent the appearance of pathogenic bacteria, eventually they only needed to directly stimulate the immune system to reach the same state.
Wait, what? Nobody wants to increase the error rate here, the point is that if the cost of the lower price is a significantly higher rate of errors, then you'll end up wasting everything else involved in getting to the point where you can check to see if you did get the correct gene in. This is only really going to save time and/or money if its accuracy is sufficiently close to being as good as the previous methods that you come out ahead in the end.
There is no real reason why quality has to drop, but even if that is the case there are quite a lot of methods for screening cheaply for desired results when you get more than you can manage (specific methods of course depending on what you are trying to do), If you already get enough samples to have to wait later then of course there is no value on getting more of them with a supposedly lower quality, but if your bottleneck is the first step then of course manufactured DNA is going to help getting the job done.
To put it in IT terms which might help here: Since DNA is in fact a means of transmitting data, my question here is entirely how the quality of service is. Do they have equal quality of service? The cheaper method, if it's got better QoS (more likely to get the sequence of bases correct) then it's definitely an improvement and the drop in price is actually probably less important--on the other hand, it might be like going from having your bytes transmitted by a guy operating a switch to attempting to do so via semaphore flags on a foggy day.
The advantages of DNA manufacturing is not evident for someone that order a single oligo to do all the subsequent job for months as it seems to be your case, because your specific application focus only on the quality of the sequence. But for people that need to try many different sequences to see which one works efficiently its gold. Trying dozens of sequences at once and getting a few positive results is then a huge advantage, even if later you need to do some kind of extra work on them to corroborate.
We're already at the point that we need a 'reliable' sequencing robot. It's worth repeating that the backlogs are pretty much universal--the demand far outstrips current capacity, but it's a laborious process which automation only makes slightly less laborious. Running the PCR machine for a few extra cycles is not really that expensive, having the equipment is, and our 'reliable' sequencing robots still have an error rate because PCR itself has an error rate.
Exactly the case when this advantage have no meaning, but a lot of people have the opposite problem, their sequencers are free a lot of time because they can't proceed to that point without first trying a lot of different oligos, something that right now is very expensive (specially when you are ordering oligos of hundreds of mer) so you have to try only a few each time to avoid waste.
As far as the people giving you grant money are concerned, 'extra experiment' and 'personal bill' are the same, and what this might do is raise your chances of getting a grant at all and/or the grant money actually being sufficient for you to do the experiment you were given it for. If you manage to somehow come out with leftovers, returning it actually may be the best idea simply because that may improve your chances in the future. (One thing I covered very, very carefully as an undergrad is what is involved in the grant process--there was rather little doubt that I'd be involved in research, the surprise was that my body decided to inform me that I was going into the computational end; I decided I'd stack and try to move to neuroscience.)
Not at all, in most grant systems you have to give a very detailed report of all your activities and results. Getting more and better results is more important than saving on money, so If you increase the impact of your results (better Journal) by using your whole grant then you will be much more likely
I did read the article, and the thing is that it won't necessarily save time or money if the error rate is higher--with what you're suggesting, if I'm going to be optimistic I might get maybe a fifth of those wells actually being a successful transformation, assuming that my host isn't one where using a 96 well plate actually will lower my success rate. I still won't know if any of those are the sequence I want until I sequence them, and the last part is pretty expensive and time-consuming, especially if you're sending it off in bulk.
Its not important to increase the error rate if the main product you are wasting is cheap DNA sequences. Lets say that you now can try 5 or 6 of them in one week, then another 5 or 6 the next week until you are successful (so you can save on DNA by ordering only the absolutely minimum amount). If you can get the oligos dirt cheap then you just order a butt load of them and try as many as you can, get this first step results much faster without so much waste. It will not matter if you get only one good transformation from a whole plate if everything you are using is cheap.
Trying a few every time may get you that single one in the first try or in the 20th try, you may save money in DNA but will have to invest much more time. If you are getting cheap DNA this changes the cost/benefit towards time as the most expensive thing you will use.
Of course if you are going large scale because you stopped worrying about how much your custom DNA is going to cost you switch into screening your results instead of processing each one all the way. No need to sequence 20 supposedly positive colonies from your plate, do a colony PCR and get maybe a 5th to confirm by sequencing, you would still have saved a lot of time even if you sequence each one so you don't waste sequencing time (or reactives).
my experience is that the time frame is in the month(s) range, especially if the lab doing it for you is swamped.
That is why I mentioned that labs without capabilities to handle the increase amount of work that becomes possible the advantages are of course much less
If your goal is to save time and money, an automated sequencer that is reliable enough and cheap enough that you can do it in-house is probably even more important than this--and that's also a PITA to do right now, since my experience is that you still have to double-check the automated ones by hand because they'll do Weird Things.
The differences is that manufactured DNA becomes cheaper without you investing anything at all, the prices come down by themselves when the company begins the service, a reliable sequencing robot will of course needs money to be put in order and its not necessary if you screen your samples and process the same number as you are doing now but chosen from a larger pool obtained in a shorter time. In many places the whole process is streamlined and one of the important things that restrict the amount of work that can be finished is doing the first steps slowly in order to avoid wasting money in unnecessary sequences.
Also, grant money is like having a company credit card with a painfully low limit: You really can't use it to cover your personal bills if you want to keep it (and your job), and if you're lucky it'll actually cover all that it was given to you to cover . So, this might make it for a time easier to actually cover more of the work with the grant money...but you're funny if you think there's going to be any left over for experiments other than what you got the grant for.
And who talked about any personal bills? I am talking about having more freedom at the first step of your work by expending less than as before but getting much more options to begin with, get results faster and begin the next step with a little more chance of covering your costs with the reduced amount you are given from the beginning (Until the powers almighty
As mentioned in the article the DNA manufacturing makes cheaper only the first part of the process and the main cost remain the same, the advance will most likely save time but not money. For example instead of running a few reaction with the 8 to 10 oligos you felt you could order that week you just make a 96 well plate of reactions each with a different one and check how many give a successful transformation. Of course if that is above your lab capacity then the advantages are not so good.
Still, if this manufacturing becomes common then other things will also become cheaper and more experiments could be done with the same grant (until the grants become smaller since DNA is cheap so you should do with half what you asked).
At least in Japanese the artificial voice is quite good, on the first few seconds its difficult to say if its a person or a machine reading the text, but eventually you begin to notice the uniformity of the tone no matter what the news are. At least for now they are choosing minor news to try it, so its not so much of a problem having the voice-over sounding happy and light while reading about dozens of dead people on a landslide or something.
??? They are using RNA, the pigs genome is unaltered, the offspring will be still "natural" pigs, the treated pigs in a few months will go back to expressing the protein and again will be vulnerable to PRSSV. People have to stop reading "genetic" as "permanent".
CD163 is a relatively well described protein with very detailed functions, mostly on innate immunity. Fortunately innate immunity have many kinds pathways that interconnect and supplement each other (probably because pathogens are very good at interfering with them) so blocking one pathway at the beginning, like in this case, would have very little effect overall and interleukin 6 and 10 (and the rest of the cascade) will be still produced. For the virus of course this lack of CD163 its lethal, but for the pig it may at much represent slightly increased rates of infections of other pathogens, many of those are no longer important since the pigs are not in the wild anymore.
Maybe not exactly like your example but more like creatures that lost their ability to run fast by overeating themselves to obesity, let loose a few bears and the fit ones will have much better chances of surviving.
Cancer cells are in general very susceptible to infection, many times you can grow viruses in cell cultures coming from organisms that are not susceptible to that virus because the cultures are cancer cells. The problem is to make the virus lethal enough to kill efficiently the cancer but tame enough so the normal cells and organs are not affected too much. Similar to live vaccines but with a much more difficult balance to keep.
That example was so bad it hurts. The position is "this data is not enough to say that these cancers were caused by radiation" that is completely different and much more rational.
Does this "fingerprint" bacterial cloud change with time? after antibiotic use? what about members of a family or people that recently began living together? It does not feel like this will have a practical use in the near future, but opens some interesting lines of study.
Maybe because it takes a higher amount of time, money and expertise to explain it? There is value in describing something that nobody else has tried, even if only to direct people with more resources to work in that.
Another reason not yet mentioned is that every adaptation is a trade off, and becomes a path that is easier to follow than beginning a new one in order to have the same advantage, chickens have a very well developed innate immunity (interferon, citoquines, etc) as well as a secondary immunity in the form of antibodies against viruses, unfortunately is not very effective against influenza. Nevertheless from the evolutionary point of view trying to improve those mechanisms of defense is much less resource intensive than beginning a new one based on genes (decoys in this case, or also interference RNA to give another example) Insects for example have the exact opposite problem since they have the direct gene based defense instead of the antibody based one.
It would be very interesting to see the Ethical committee discussion when they approved the study, I bet they are convinced that "anonymizing" the calls means impossible to identify by any means.
Its exactly like this with some extra options when making the contracts in special sales (I got a second hand Washing machine). They do require you to install some useless things in your computer to use the service but at least has been problem free the whole time I have been using it.
It is not clear how the new nucleotides act when transcribing proteins but assuming its at least as efficient as the 4 letter code it could be a very interesting option for artificial viruses. A virus engineered to be totally dependent on the new nucleotides could be used much more safely even inside humans where there is no supply of them, they could infect the cells, produce proteins and a huge immune response but not a single copy of their genetic material could be produced. Also in a controlled environment they would thrive (cheap production?) but without P-Z no danger of new virus production so safety would not need to be as strict.
Applications on real organisms probably will take much longer time, but the simplicity of virus would make it a natural first step.
There are a lot of medical interventions that are very nice on paper but useless in practice because of the difficulty of delivering something fragile to a specific point in the body. This super-vesicles seem to be still too limited to address this problem perfectly but they seem like a big step forward, a couple of generations later this could very well make gene-therapy, siRNA inhibition, cell-specific drug therapies, etc. practical enough to be used as therapy.
Slashdot Mirror
The problem is that they did not plan realistically, $25K to replicate these kind of experiments by an external lab is not doable. They took the best case scenario (what would it cost for the people that already did it once and have all the details solved) and tried to apply it to the worst case scenario (do it again by different people, with different equipment, without lots of necessary information, etc.)
sure, as long as you ignore the vast mayority of the people that get infected with SFTSV and never get more than a slight fever for some days.
These kind of chimeras are not necessary for this kind of risky situation, experimental animals are right now routinely "humanized" by modifying their genome in order for them to express human proteins, this makes the humanized animals susceptible to some human diseases and theoretically facilitates the appearance of pathogens that can now infect humans (specially viruses). The new chimeras of this post are actually safer since their offspring would not carry any human traits so they can't be mass produced.
At the beginning it was all very fuzzy and cases very uncharacteristic for viruses of the same family, but the research that has been done in the last few months is admirable, it is now completely clear that, even if it was unexpected, Zika acts like its mild fever type of related virus in adults (like Dengue and Yellow Fever) but becomes much more like the neurocentric cousins of the family in embryos (like West Nile and Japanese Encephalitis). Anybody that is following the reports, even if only the titles, was expecting this conclusion from the CDC and WHO.
I mean, this has been studied for many examples in the past but this experimental design results put a lot more weigh on this theory. I could not find the original article so I don't know what they used as a control, but as long as they deleted also equivalent sequences of the genome (not ERVs) without observing the drop of immunity this approach would clearly demonstrate this mechanism.
I understood the paper differently, researchers used gut viruses to trick the mouse immune system to go into a "colonization resistance" state that prevent the appearance of pathogenic bacteria, eventually they only needed to directly stimulate the immune system to reach the same state.
Wait, what? Nobody wants to increase the error rate here, the point is that if the cost of the lower price is a significantly higher rate of errors, then you'll end up wasting everything else involved in getting to the point where you can check to see if you did get the correct gene in. This is only really going to save time and/or money if its accuracy is sufficiently close to being as good as the previous methods that you come out ahead in the end.
There is no real reason why quality has to drop, but even if that is the case there are quite a lot of methods for screening cheaply for desired results when you get more than you can manage (specific methods of course depending on what you are trying to do), If you already get enough samples to have to wait later then of course there is no value on getting more of them with a supposedly lower quality, but if your bottleneck is the first step then of course manufactured DNA is going to help getting the job done.
To put it in IT terms which might help here: Since DNA is in fact a means of transmitting data, my question here is entirely how the quality of service is. Do they have equal quality of service? The cheaper method, if it's got better QoS (more likely to get the sequence of bases correct) then it's definitely an improvement and the drop in price is actually probably less important--on the other hand, it might be like going from having your bytes transmitted by a guy operating a switch to attempting to do so via semaphore flags on a foggy day.
The advantages of DNA manufacturing is not evident for someone that order a single oligo to do all the subsequent job for months as it seems to be your case, because your specific application focus only on the quality of the sequence. But for people that need to try many different sequences to see which one works efficiently its gold. Trying dozens of sequences at once and getting a few positive results is then a huge advantage, even if later you need to do some kind of extra work on them to corroborate.
We're already at the point that we need a 'reliable' sequencing robot. It's worth repeating that the backlogs are pretty much universal--the demand far outstrips current capacity, but it's a laborious process which automation only makes slightly less laborious. Running the PCR machine for a few extra cycles is not really that expensive, having the equipment is, and our 'reliable' sequencing robots still have an error rate because PCR itself has an error rate.
Exactly the case when this advantage have no meaning, but a lot of people have the opposite problem, their sequencers are free a lot of time because they can't proceed to that point without first trying a lot of different oligos, something that right now is very expensive (specially when you are ordering oligos of hundreds of mer) so you have to try only a few each time to avoid waste.
As far as the people giving you grant money are concerned, 'extra experiment' and 'personal bill' are the same, and what this might do is raise your chances of getting a grant at all and/or the grant money actually being sufficient for you to do the experiment you were given it for. If you manage to somehow come out with leftovers, returning it actually may be the best idea simply because that may improve your chances in the future. (One thing I covered very, very carefully as an undergrad is what is involved in the grant process--there was rather little doubt that I'd be involved in research, the surprise was that my body decided to inform me that I was going into the computational end; I decided I'd stack and try to move to neuroscience.)
Not at all, in most grant systems you have to give a very detailed report of all your activities and results. Getting more and better results is more important than saving on money, so If you increase the impact of your results (better Journal) by using your whole grant then you will be much more likely
Maybe the people that order sequences of several hundred of bases? If I need 500mer oligos $10+SnH looks much better than 400+SnH.
I did read the article, and the thing is that it won't necessarily save time or money if the error rate is higher--with what you're suggesting, if I'm going to be optimistic I might get maybe a fifth of those wells actually being a successful transformation, assuming that my host isn't one where using a 96 well plate actually will lower my success rate. I still won't know if any of those are the sequence I want until I sequence them, and the last part is pretty expensive and time-consuming, especially if you're sending it off in bulk.
Its not important to increase the error rate if the main product you are wasting is cheap DNA sequences. Lets say that you now can try 5 or 6 of them in one week, then another 5 or 6 the next week until you are successful (so you can save on DNA by ordering only the absolutely minimum amount). If you can get the oligos dirt cheap then you just order a butt load of them and try as many as you can, get this first step results much faster without so much waste. It will not matter if you get only one good transformation from a whole plate if everything you are using is cheap.
Trying a few every time may get you that single one in the first try or in the 20th try, you may save money in DNA but will have to invest much more time. If you are getting cheap DNA this changes the cost/benefit towards time as the most expensive thing you will use.
Of course if you are going large scale because you stopped worrying about how much your custom DNA is going to cost you switch into screening your results instead of processing each one all the way. No need to sequence 20 supposedly positive colonies from your plate, do a colony PCR and get maybe a 5th to confirm by sequencing, you would still have saved a lot of time even if you sequence each one so you don't waste sequencing time (or reactives).
my experience is that the time frame is in the month(s) range, especially if the lab doing it for you is swamped.
That is why I mentioned that labs without capabilities to handle the increase amount of work that becomes possible the advantages are of course much less
If your goal is to save time and money, an automated sequencer that is reliable enough and cheap enough that you can do it in-house is probably even more important than this--and that's also a PITA to do right now, since my experience is that you still have to double-check the automated ones by hand because they'll do Weird Things.
The differences is that manufactured DNA becomes cheaper without you investing anything at all, the prices come down by themselves when the company begins the service, a reliable sequencing robot will of course needs money to be put in order and its not necessary if you screen your samples and process the same number as you are doing now but chosen from a larger pool obtained in a shorter time. In many places the whole process is streamlined and one of the important things that restrict the amount of work that can be finished is doing the first steps slowly in order to avoid wasting money in unnecessary sequences.
Also, grant money is like having a company credit card with a painfully low limit: You really can't use it to cover your personal bills if you want to keep it (and your job), and if you're lucky it'll actually cover all that it was given to you to cover . So, this might make it for a time easier to actually cover more of the work with the grant money...but you're funny if you think there's going to be any left over for experiments other than what you got the grant for.
And who talked about any personal bills? I am talking about having more freedom at the first step of your work by expending less than as before but getting much more options to begin with, get results faster and begin the next step with a little more chance of covering your costs with the reduced amount you are given from the beginning (Until the powers almighty
As mentioned in the article the DNA manufacturing makes cheaper only the first part of the process and the main cost remain the same, the advance will most likely save time but not money. For example instead of running a few reaction with the 8 to 10 oligos you felt you could order that week you just make a 96 well plate of reactions each with a different one and check how many give a successful transformation. Of course if that is above your lab capacity then the advantages are not so good.
Still, if this manufacturing becomes common then other things will also become cheaper and more experiments could be done with the same grant (until the grants become smaller since DNA is cheap so you should do with half what you asked).
At least in Japanese the artificial voice is quite good, on the first few seconds its difficult to say if its a person or a machine reading the text, but eventually you begin to notice the uniformity of the tone no matter what the news are. At least for now they are choosing minor news to try it, so its not so much of a problem having the voice-over sounding happy and light while reading about dozens of dead people on a landslide or something.
whops, wrong topic, never mind.
???
They are using RNA, the pigs genome is unaltered, the offspring will be still "natural" pigs, the treated pigs in a few months will go back to expressing the protein and again will be vulnerable to PRSSV. People have to stop reading "genetic" as "permanent".
CD163 is a relatively well described protein with very detailed functions, mostly on innate immunity. Fortunately innate immunity have many kinds pathways that interconnect and supplement each other (probably because pathogens are very good at interfering with them) so blocking one pathway at the beginning, like in this case, would have very little effect overall and interleukin 6 and 10 (and the rest of the cascade) will be still produced. For the virus of course this lack of CD163 its lethal, but for the pig it may at much represent slightly increased rates of infections of other pathogens, many of those are no longer important since the pigs are not in the wild anymore.
Maybe not exactly like your example but more like creatures that lost their ability to run fast by overeating themselves to obesity, let loose a few bears and the fit ones will have much better chances of surviving.
Cancer cells are in general very susceptible to infection, many times you can grow viruses in cell cultures coming from organisms that are not susceptible to that virus because the cultures are cancer cells. The problem is to make the virus lethal enough to kill efficiently the cancer but tame enough so the normal cells and organs are not affected too much. Similar to live vaccines but with a much more difficult balance to keep.
That example was so bad it hurts. The position is "this data is not enough to say that these cancers were caused by radiation" that is completely different and much more rational.
Does this "fingerprint" bacterial cloud change with time? after antibiotic use? what about members of a family or people that recently began living together? It does not feel like this will have a practical use in the near future, but opens some interesting lines of study.
Maybe because it takes a higher amount of time, money and expertise to explain it? There is value in describing something that nobody else has tried, even if only to direct people with more resources to work in that.
Another reason not yet mentioned is that every adaptation is a trade off, and becomes a path that is easier to follow than beginning a new one in order to have the same advantage, chickens have a very well developed innate immunity (interferon, citoquines, etc) as well as a secondary immunity in the form of antibodies against viruses, unfortunately is not very effective against influenza. Nevertheless from the evolutionary point of view trying to improve those mechanisms of defense is much less resource intensive than beginning a new one based on genes (decoys in this case, or also interference RNA to give another example) Insects for example have the exact opposite problem since they have the direct gene based defense instead of the antibody based one.
It would be very interesting to see the Ethical committee discussion when they approved the study, I bet they are convinced that "anonymizing" the calls means impossible to identify by any means.
I like how in the article they say that the design is an improvement over the 2012 model, because they looked "dorky"
Its exactly like this with some extra options when making the contracts in special sales (I got a second hand Washing machine).
They do require you to install some useless things in your computer to use the service but at least has been problem free the whole time I have been using it.
It is not clear how the new nucleotides act when transcribing proteins but assuming its at least as efficient as the 4 letter code it could be a very interesting option for artificial viruses. A virus engineered to be totally dependent on the new nucleotides could be used much more safely even inside humans where there is no supply of them, they could infect the cells, produce proteins and a huge immune response but not a single copy of their genetic material could be produced. Also in a controlled environment they would thrive (cheap production?) but without P-Z no danger of new virus production so safety would not need to be as strict.
Applications on real organisms probably will take much longer time, but the simplicity of virus would make it a natural first step.
This is what came to my mind immediately when reading the title, for both kinds of rats.
There are a lot of medical interventions that are very nice on paper but useless in practice because of the difficulty of delivering something fragile to a specific point in the body. This super-vesicles seem to be still too limited to address this problem perfectly but they seem like a big step forward, a couple of generations later this could very well make gene-therapy, siRNA inhibition, cell-specific drug therapies, etc. practical enough to be used as therapy.