Making stem cells
Sep. 26th, 2014 04:20 pm![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
livA while back, I made a post about why epigenetics is important. And one of the reasons is because understanding epigenetics means that we can reprogram mature cells into stem cells. I ran out of time and space to write about this breakthrough and its implications in my last post, so I'm going to have a go at following up now.
Induced stem cells
Cells have different levels of potency, which means how many fates are possible for them. Cells from the early embryo are totipotent, meaning they can become literally any cell type, including the placenta as well as parts of the future person. Most of the stem cells that persist beyond the first few weeks of embryo development are pluripotent, multipotent or oligopotent, which are increasingly restricted in what they can develop into. And terminally differentiated cells are those that are actually doing a job in the body rather than dividing to produce more cells. Which is the great majority of all cells in adults. For most of the 20th century it was dogma that you couldn't reverse this timeline, cells can only get more and more restricted in their fate options and once they've committed to a particular branch of development, never go backwards. This is still basically true in terms of what actually happens naturally, but it turns out that it is possible to intervene and artificially turn more specialist cells into more general-purpose stem cells.
In the mid-90s Ian Wilmut and Keith Campbell cloned Dolly the sheep using a nucleus from an adult, terminally differentiated cell, but this is a massively technically intensive process with a low success rate. But this, along with increased understanding of epigenetics, opened the way to loads of new research into technologies previously thought impossible, so that in the mid 2000s, Shinya Yamanaka and his colleagues discovered that it's possible, and relatively speaking technically simple, to take mature, terminally differentiated cells and manipulate their epigenetic patterns to turn them back into at least pluripotent stem cells.
In terms of potential for medical applications, this is seriously revolutionary, yet doesn't seem to be getting nearly as much buzz as, say, robotics tech allowing paralysed people to manipulate their environment.
What's the point?
OK, so you can take some mature cells which are easy to get at and can easily be spared, let's say skin cells. And you can reprogram them so they're not skin cells any more, they're pluripotent stem cells. Because they're stem cells, they will divide, so you can easily get more of them, potentially even billions of cells if that's what you need. And you can give them the appropriate hormones and chemicals so that they turn into just about any kind of cells you might need. Even nerve cells, which are notorious for having really low regeneration power (in fact many textbooks will state categorically but technically not correctly that brain cells don't regenerate at all.) You can genetically manipulate those cells if you want to, without fear that your genetic tinkering will be passed on to another generation. You can then transplant the cells back into the person they came from, so there will be no problems with immune rejection. As stem cells, they will regenerate injured or damaged tissues, maybe even grow new organs.
This means that previously irreversible injuries and degenerative conditions might be curable. It means a possibility of curing genetic diseases, which we've been trying to do for decades with almost no success. Because it's really hard to change the genome of cells and tissues within the body, but relatively quite easy to change the genome of extracted cells, which can then be transplanted back with their genetic defect fixed. It means that many of the problems of organ donation (shortage of donor organs, finding a match etc) can potentially be bypassed. And this is possible without needing to use material from aborted foetuses, or needing to create foetuses specifically for the purpose of harvesting stem cells, both of which are ethically contested. Instead the stem cells can come directly from the patient who needs them, or a consenting adult donor in some cases. And donating a few cells is much less of a scary prospect than donating a whole organ!
Cell-based treatments
So let's talk about specifics, it's easy enough to speculate what we might be able to do with an effectively unlimited supply of stem cells, but what actually works works in the real world? I have a lot of colleagues in my institution who work on this stuff, so I have been hearing quite a lot about it, and I'd like to tell you some of the cool things that are being pioneered here and elsewhere. Just 8 years after Yamanaka's discovery, we have a few actual real-world induced pluripotent stem cell based treatments being used in real patients, still in early phase trials but actual human beings are getting benefits from this stuff.
Regenerating damaged joints
People whose knees aren't functional, whether from progressive diseases like arthritis or because of injury, get pain relief, mobility aids and adaptations, and eventually may qualify for joint replacements. Making and implanting an artificial joint is really cool, but it's major surgery, and the artificial joints give out after 5-10 years, and don't give full functionality. It would be better in many ways if we could persuade the body to repair or regrow a natural joint. So for about 15 years ish, a few specialist hospitals have been injecting cartilage-forming cells into joints. (This is called autologous chondrocyte implantation, if you want to know more.) So the surgical technique is already established, but you have to have two lots of bone surgery, one to remove the cartilage-forming cells from elsewhere in the body, and one to implant them in the damaged joint. And cartilage-forming cells are quite rare anyway. A logical extension of this is to take cells which are plentiful and easy to get at, (eg fat cells) and reprogram them into induced stem cells, which can be directed to form a basically unlimited supply of chondrocytes to help repair the damaged joints.
Potential treatment for Duchenne's Muscular Dystrophy
This basically blew my mind when I heard about it. DMD is an incurable and untreatable, progressive genetic condition. From the age of 3–5, boys with this disease start to lose muscle function, first in the big load-bearing muscles like legs, and then other muscles follow leading to continuously decreasing mobility and function until eventually even breathing is impossible. With good medical care people with DMD can live into their late teens or early 20s, but with very high levels of pain and disability. There's nothing you can do about it with conventional treatments, because it's genetic and every single cell of every muscle is affected. And people have been trying for years to treat it with genetic engineering, it's in theory promising because we know exactly which single gene mutation causes the disease, and although it's rare in absolute terms it's common compared to genetic diseases. But it's pretty clearly not working, partly because the gene itself is huge and therefore hard to fix, and partly because even if you can fix it there's no way to get the fixed gene into all the muscles of the body, and even if you could overcome that technical barrier, that wouldn't repair the damage already done to muscles with the mutation.
So there's this new approach which involves taking accessible cells from a donor, say the brother of the kid with the disease. Turning them back into stem cells, growing them up in large amounts, and directing them to grow into a special kind of late-stage stem cell called a satellite cell. The thing with DMD is that the muscles initially develop normally, but are extremely fragile and easily become damaged, just through general daily use without any injury, because they don't have the protein that holds the strongest parts of the muscle together. At first the damage is repaired by satellite cells, resident stem cells whose normal job is to repair muscles. But satellite cells run out, because they differentiate into muscle cells to replace the damaged ones, and the body has a finite supply of them.
However, this one Italian doctor grew up a supply of new satellite cells from induced stem cells, and injected them back into the muscles of some 10-year-olds with DMD. Tiny trial, I'm talking 5 boys, and no control group because it's not the kind of experiment you can ethically do as a double-blind trial. Of the 5, one didn't get any benefit from the treatment, and four got slight improvements but more importantly got 2–3 years when their symptoms didn't get any worse. Until they hit puberty and testosterone meant that their muscles grew faster than could be sustained with the genetic defect, they didn't lose any functional abilities. The "control" in this case, and yes, it's a weak one, is typical children with DMD, who would normally see considerable increases in disability from aged 10 to early teens; that's typically the time when kids lose any residual ability to walk and start needing to use motorized wheelchairs.
Stuff that's in development, most of this is still at the proof of concept / animal trials stage, but it's looking promising:
Treating Parkinson's disease
So in Parkinson's disease people lose a very specific type of neurones, those that secrete dopamine. This causes a bunch of motor problems, shakiness and trembling initially, and rigidity, freezing and inability to initiate movement, and there are psychiatric, mood and cognitive problems as well, including eventually dementia. The neurones die and never get replaced, so the disease only gets worse, though the symptoms can be controlled somewhat by giving people dopamine as a drug. People have been trying for a while to treat PD with stem cells, but sourcing enough stem cells was a real problem. So the concept is to take cells from the patients themselves, meaning no problems of immune rejection, reprogram them into neural stem cells, grow them up so there are enough to replace the substantia nigra region of the brain, and transplant them back into the brain so that they can form new dopamine neurones. So far this works in rodents, and well enough that you can probably expect to see the first human trials in the next few years.
Eye diseases
There's a lot of work about basically growing replacement corneas. Yes, corneas can sometimes be transplanted from recently deceased donors, but there aren't enough to provide transplants for everybody who has genetic or sustained corneal damage. I haven't been following this really closely because I'm horribly squeamish about eyes, but there are biotech companies getting venture capital investment on the basis that the technology is more or less in place to be able to grow corneas pretty much on demand from induced stem cells, and sell them as an off-the-shelf product.
Bone repair
Most fractures pretty much heal themselves, if appropriately fixed, because bone naturally contains cells capable of remodelling and regrowing bone. But really huge injuries, either from explosives or from major bone cancer, are beyond the capacity of the body's natural repair system. Currently the best option is to graft bone from other places in the body, but honestly there isn't all that much spare bone, plus as with the joint stuff it means double surgery. So the concept is to take accessible cells, program them into induced stem cells, grow up as many as you need (which might be far more than ever exist naturally in the skeleton), differentiate them into bone-forming cells, and implant those to repair the injury. Again, it works in animals.
Nerve repair
I'm super-excited about this one. Basically you can take a rat, sever its spinal cord with a scalpel, implant induced or natural stem cells at the site of injury, and the spine will grow back, giving you a rat that can run about quite happily with few measurable differences from its fellow rats that never had their spines broken. Now clearly, this is quite a different situation from somebody who actually sustains a spinal injury; normally it's not a clean surgical cut like the ones in the animal studies, and normally there aren't stem cells right there to apply within minutes of the injury, before the damage has had a chance to spread. But it does at least give some hope that one day spinal cord injury might be treatable, if the technology matures.
Actually a lot of this is a materials problem as much as a stem cell thing; nerves, contrary to what you probably learned in school, do have the capacity for regrowth and repair. There are even some natural neural stem cells in some parts of the body. The problem is that if the injury is bigger than a few mm, it's really hard for the regrowing axons to make connections and "find" the other neurones they're supposed to link up to. During development there are systems of chemical guides which make sure all the nerves grow in the right direction, but those aren't present after nerve injury. So a lot of the work in this area is about making scaffolds and tubes and fibres and magnetic guides that can be impregnated with stem cells, making sure that the new nerves grow across the gap and join on to the existing nerves the other side of the injury.
Still, if it can be done with spines which are immensely complicated, it's even closer to possible to repair peripheral nerves. Like when someone's hand gets deeply cut or crushed in an accident, if the nerves can be persuaded, with the help of stem-cell impregnated scaffolds, to grow back, then they may well get their the function of their fingers back. Currently small nerve injuries can sometimes be fixed by means of extremely skilled surgeons literally suturing the severed nerves back together, but nerves are really not very stretchy so this isn't practical if the gap is bigger than a few mm. Nerve grafts, again surgically removing material from another part of the body, and really there's no such thing as an unneeded nerve, are one way that these major injuries are sometimes patched up at the moment. But if the technology matures, stem cells might be technically easier and more effective for repair.
Other organs
I've heard people talking about using stem cells to repair or replace all kinds of things, nephrons for improving filtration in damaged kidneys, hepatocytes in livers damaged by alcohol disease or physical injury, insulin-secreting islets in the pancreas, even heart muscle. This is all really experimental at the moment, but it's true that induced stem cells can be persuaded to grow into all these types of cells, and they're functional in lab assays. Whether they can actually be transplanted back into damaged organs and actually repair them, who knows?
We are already starting to see some indirect benefits because these stem-cell derived synthetic tissues are a much better model for testing drugs than just plain cells, because they contain a mixture of cell types and are three-dimensional. Also both more ethical and more realistic than animal studies, and there's the additional benefit that you can make your test system out of cells from the specific patient you're trying to treat, so you can see if you drug works for them, rather than only whether it works for people on average. My guess is that some of these technologies will pan out and be clinically useful, others won't, but even the distant hypothetical prospect of being able to regenerate the parts of the pancreas that are damaged by autoimmune reactions in Type I diabetes or build-up of mucus in cystic fibrosis would have seemed impossible before the stem cell era and pretty implausible if we had to rely on embryonic stem cells which are in limited supply.
Science fiction
Well, this is all very rosy, and it's easy to get carried away speculating wildly about being able to repair any damage, sculpt bodies and body mods according to whim etc. Scientists are just as guilty of getting carried away as the the general public, because the technique really is powerful on levels we just couldn't have imagined before now.
I don't want to tell you this will never happen, but with current and readily foreseeable from here technology, we can't actually regenerate whole limbs or organs. The cutting edge at the moment is things like pancreatic islets and nephrons, which are already made of a mixture of three or four different cell types, and extremely technically tricky to reconstitute, because you need three dimensional structures, not just populations of cells. But there's a lot you can do with just single cell types, whether that's nerves, cartilage, corneas, bone, muscle etc, and we're only just starting to imagine what might be possible with this technology.
Scaling up is definitely still an issue. In principle you can get infinite amounts of induced stem cells, but the actual practicalities of doing that are still very much in the early days. Partly because if you just leave stem cells growing in the lab they very quickly cease to be stem cells, and either become tumour forming cells or differentiate by themselves into cell types you might not want instead of the desired ones. There is some evidence that even tiny amounts of stem cells may be medically useful, because they secrete chemical messengers called cytokines which attract other stem cells and promote growth and repair. But if we're talking regrowing a whole liver we probably need several billion cells, not just a few tens of thousand.
Obviously since only a very few patients have been treated with stem cells, and only very recently, we don't know about long-term side effects. So far the safety profile looks good, but we will only know it's really safe once the technology is mature enough to have been tried on millions of patients over the course of decades. The big thing that people are worried about is that implanted stem cells may give rise to tumours. So far it seems like induced stem cells have less risk of turning into cancer than embryonic stem cells, partly because they don't have the same proliferative capacity.
We also can't reverse ageing or grow new clone bodies. Again, it's looking sliiiightly more possible than it seemed a couple of decades ago, but at very least we would need a whole lot better understanding of how cells interact and combine to form tissues and organs than we currently have. Plus a better understanding of what ageing actually is, and it's probably a combination of many different processes. What's clear is that cell ageing, where cells shorten their chromosome telomeres and lose their capacity to divide, is only part of story of body ageing. (And we have no idea at all how to "transplant" someone's personality / memories / brain into a new body; this may never be possible, and if it does become possible it probably won't be because of stem cells)
I was really charmed by the enthusiastic response to my previous post in this quasi-series. So please do ask more of those excellent questions that you were asking before. I can provide more broken-down explanations or links to peer-reviewed sources, depending what level you're at.
Induced stem cells
Cells have different levels of potency, which means how many fates are possible for them. Cells from the early embryo are totipotent, meaning they can become literally any cell type, including the placenta as well as parts of the future person. Most of the stem cells that persist beyond the first few weeks of embryo development are pluripotent, multipotent or oligopotent, which are increasingly restricted in what they can develop into. And terminally differentiated cells are those that are actually doing a job in the body rather than dividing to produce more cells. Which is the great majority of all cells in adults. For most of the 20th century it was dogma that you couldn't reverse this timeline, cells can only get more and more restricted in their fate options and once they've committed to a particular branch of development, never go backwards. This is still basically true in terms of what actually happens naturally, but it turns out that it is possible to intervene and artificially turn more specialist cells into more general-purpose stem cells.
In the mid-90s Ian Wilmut and Keith Campbell cloned Dolly the sheep using a nucleus from an adult, terminally differentiated cell, but this is a massively technically intensive process with a low success rate. But this, along with increased understanding of epigenetics, opened the way to loads of new research into technologies previously thought impossible, so that in the mid 2000s, Shinya Yamanaka and his colleagues discovered that it's possible, and relatively speaking technically simple, to take mature, terminally differentiated cells and manipulate their epigenetic patterns to turn them back into at least pluripotent stem cells.
In terms of potential for medical applications, this is seriously revolutionary, yet doesn't seem to be getting nearly as much buzz as, say, robotics tech allowing paralysed people to manipulate their environment.
What's the point?
OK, so you can take some mature cells which are easy to get at and can easily be spared, let's say skin cells. And you can reprogram them so they're not skin cells any more, they're pluripotent stem cells. Because they're stem cells, they will divide, so you can easily get more of them, potentially even billions of cells if that's what you need. And you can give them the appropriate hormones and chemicals so that they turn into just about any kind of cells you might need. Even nerve cells, which are notorious for having really low regeneration power (in fact many textbooks will state categorically but technically not correctly that brain cells don't regenerate at all.) You can genetically manipulate those cells if you want to, without fear that your genetic tinkering will be passed on to another generation. You can then transplant the cells back into the person they came from, so there will be no problems with immune rejection. As stem cells, they will regenerate injured or damaged tissues, maybe even grow new organs.
This means that previously irreversible injuries and degenerative conditions might be curable. It means a possibility of curing genetic diseases, which we've been trying to do for decades with almost no success. Because it's really hard to change the genome of cells and tissues within the body, but relatively quite easy to change the genome of extracted cells, which can then be transplanted back with their genetic defect fixed. It means that many of the problems of organ donation (shortage of donor organs, finding a match etc) can potentially be bypassed. And this is possible without needing to use material from aborted foetuses, or needing to create foetuses specifically for the purpose of harvesting stem cells, both of which are ethically contested. Instead the stem cells can come directly from the patient who needs them, or a consenting adult donor in some cases. And donating a few cells is much less of a scary prospect than donating a whole organ!
Cell-based treatments
So let's talk about specifics, it's easy enough to speculate what we might be able to do with an effectively unlimited supply of stem cells, but what actually works works in the real world? I have a lot of colleagues in my institution who work on this stuff, so I have been hearing quite a lot about it, and I'd like to tell you some of the cool things that are being pioneered here and elsewhere. Just 8 years after Yamanaka's discovery, we have a few actual real-world induced pluripotent stem cell based treatments being used in real patients, still in early phase trials but actual human beings are getting benefits from this stuff.
People whose knees aren't functional, whether from progressive diseases like arthritis or because of injury, get pain relief, mobility aids and adaptations, and eventually may qualify for joint replacements. Making and implanting an artificial joint is really cool, but it's major surgery, and the artificial joints give out after 5-10 years, and don't give full functionality. It would be better in many ways if we could persuade the body to repair or regrow a natural joint. So for about 15 years ish, a few specialist hospitals have been injecting cartilage-forming cells into joints. (This is called autologous chondrocyte implantation, if you want to know more.) So the surgical technique is already established, but you have to have two lots of bone surgery, one to remove the cartilage-forming cells from elsewhere in the body, and one to implant them in the damaged joint. And cartilage-forming cells are quite rare anyway. A logical extension of this is to take cells which are plentiful and easy to get at, (eg fat cells) and reprogram them into induced stem cells, which can be directed to form a basically unlimited supply of chondrocytes to help repair the damaged joints.
This basically blew my mind when I heard about it. DMD is an incurable and untreatable, progressive genetic condition. From the age of 3–5, boys with this disease start to lose muscle function, first in the big load-bearing muscles like legs, and then other muscles follow leading to continuously decreasing mobility and function until eventually even breathing is impossible. With good medical care people with DMD can live into their late teens or early 20s, but with very high levels of pain and disability. There's nothing you can do about it with conventional treatments, because it's genetic and every single cell of every muscle is affected. And people have been trying for years to treat it with genetic engineering, it's in theory promising because we know exactly which single gene mutation causes the disease, and although it's rare in absolute terms it's common compared to genetic diseases. But it's pretty clearly not working, partly because the gene itself is huge and therefore hard to fix, and partly because even if you can fix it there's no way to get the fixed gene into all the muscles of the body, and even if you could overcome that technical barrier, that wouldn't repair the damage already done to muscles with the mutation.
So there's this new approach which involves taking accessible cells from a donor, say the brother of the kid with the disease. Turning them back into stem cells, growing them up in large amounts, and directing them to grow into a special kind of late-stage stem cell called a satellite cell. The thing with DMD is that the muscles initially develop normally, but are extremely fragile and easily become damaged, just through general daily use without any injury, because they don't have the protein that holds the strongest parts of the muscle together. At first the damage is repaired by satellite cells, resident stem cells whose normal job is to repair muscles. But satellite cells run out, because they differentiate into muscle cells to replace the damaged ones, and the body has a finite supply of them.
However, this one Italian doctor grew up a supply of new satellite cells from induced stem cells, and injected them back into the muscles of some 10-year-olds with DMD. Tiny trial, I'm talking 5 boys, and no control group because it's not the kind of experiment you can ethically do as a double-blind trial. Of the 5, one didn't get any benefit from the treatment, and four got slight improvements but more importantly got 2–3 years when their symptoms didn't get any worse. Until they hit puberty and testosterone meant that their muscles grew faster than could be sustained with the genetic defect, they didn't lose any functional abilities. The "control" in this case, and yes, it's a weak one, is typical children with DMD, who would normally see considerable increases in disability from aged 10 to early teens; that's typically the time when kids lose any residual ability to walk and start needing to use motorized wheelchairs.
Stuff that's in development, most of this is still at the proof of concept / animal trials stage, but it's looking promising:
So in Parkinson's disease people lose a very specific type of neurones, those that secrete dopamine. This causes a bunch of motor problems, shakiness and trembling initially, and rigidity, freezing and inability to initiate movement, and there are psychiatric, mood and cognitive problems as well, including eventually dementia. The neurones die and never get replaced, so the disease only gets worse, though the symptoms can be controlled somewhat by giving people dopamine as a drug. People have been trying for a while to treat PD with stem cells, but sourcing enough stem cells was a real problem. So the concept is to take cells from the patients themselves, meaning no problems of immune rejection, reprogram them into neural stem cells, grow them up so there are enough to replace the substantia nigra region of the brain, and transplant them back into the brain so that they can form new dopamine neurones. So far this works in rodents, and well enough that you can probably expect to see the first human trials in the next few years.
There's a lot of work about basically growing replacement corneas. Yes, corneas can sometimes be transplanted from recently deceased donors, but there aren't enough to provide transplants for everybody who has genetic or sustained corneal damage. I haven't been following this really closely because I'm horribly squeamish about eyes, but there are biotech companies getting venture capital investment on the basis that the technology is more or less in place to be able to grow corneas pretty much on demand from induced stem cells, and sell them as an off-the-shelf product.
Most fractures pretty much heal themselves, if appropriately fixed, because bone naturally contains cells capable of remodelling and regrowing bone. But really huge injuries, either from explosives or from major bone cancer, are beyond the capacity of the body's natural repair system. Currently the best option is to graft bone from other places in the body, but honestly there isn't all that much spare bone, plus as with the joint stuff it means double surgery. So the concept is to take accessible cells, program them into induced stem cells, grow up as many as you need (which might be far more than ever exist naturally in the skeleton), differentiate them into bone-forming cells, and implant those to repair the injury. Again, it works in animals.
I'm super-excited about this one. Basically you can take a rat, sever its spinal cord with a scalpel, implant induced or natural stem cells at the site of injury, and the spine will grow back, giving you a rat that can run about quite happily with few measurable differences from its fellow rats that never had their spines broken. Now clearly, this is quite a different situation from somebody who actually sustains a spinal injury; normally it's not a clean surgical cut like the ones in the animal studies, and normally there aren't stem cells right there to apply within minutes of the injury, before the damage has had a chance to spread. But it does at least give some hope that one day spinal cord injury might be treatable, if the technology matures.
Actually a lot of this is a materials problem as much as a stem cell thing; nerves, contrary to what you probably learned in school, do have the capacity for regrowth and repair. There are even some natural neural stem cells in some parts of the body. The problem is that if the injury is bigger than a few mm, it's really hard for the regrowing axons to make connections and "find" the other neurones they're supposed to link up to. During development there are systems of chemical guides which make sure all the nerves grow in the right direction, but those aren't present after nerve injury. So a lot of the work in this area is about making scaffolds and tubes and fibres and magnetic guides that can be impregnated with stem cells, making sure that the new nerves grow across the gap and join on to the existing nerves the other side of the injury.
Still, if it can be done with spines which are immensely complicated, it's even closer to possible to repair peripheral nerves. Like when someone's hand gets deeply cut or crushed in an accident, if the nerves can be persuaded, with the help of stem-cell impregnated scaffolds, to grow back, then they may well get their the function of their fingers back. Currently small nerve injuries can sometimes be fixed by means of extremely skilled surgeons literally suturing the severed nerves back together, but nerves are really not very stretchy so this isn't practical if the gap is bigger than a few mm. Nerve grafts, again surgically removing material from another part of the body, and really there's no such thing as an unneeded nerve, are one way that these major injuries are sometimes patched up at the moment. But if the technology matures, stem cells might be technically easier and more effective for repair.
I've heard people talking about using stem cells to repair or replace all kinds of things, nephrons for improving filtration in damaged kidneys, hepatocytes in livers damaged by alcohol disease or physical injury, insulin-secreting islets in the pancreas, even heart muscle. This is all really experimental at the moment, but it's true that induced stem cells can be persuaded to grow into all these types of cells, and they're functional in lab assays. Whether they can actually be transplanted back into damaged organs and actually repair them, who knows?
We are already starting to see some indirect benefits because these stem-cell derived synthetic tissues are a much better model for testing drugs than just plain cells, because they contain a mixture of cell types and are three-dimensional. Also both more ethical and more realistic than animal studies, and there's the additional benefit that you can make your test system out of cells from the specific patient you're trying to treat, so you can see if you drug works for them, rather than only whether it works for people on average. My guess is that some of these technologies will pan out and be clinically useful, others won't, but even the distant hypothetical prospect of being able to regenerate the parts of the pancreas that are damaged by autoimmune reactions in Type I diabetes or build-up of mucus in cystic fibrosis would have seemed impossible before the stem cell era and pretty implausible if we had to rely on embryonic stem cells which are in limited supply.
Science fiction
Well, this is all very rosy, and it's easy to get carried away speculating wildly about being able to repair any damage, sculpt bodies and body mods according to whim etc. Scientists are just as guilty of getting carried away as the the general public, because the technique really is powerful on levels we just couldn't have imagined before now.
I don't want to tell you this will never happen, but with current and readily foreseeable from here technology, we can't actually regenerate whole limbs or organs. The cutting edge at the moment is things like pancreatic islets and nephrons, which are already made of a mixture of three or four different cell types, and extremely technically tricky to reconstitute, because you need three dimensional structures, not just populations of cells. But there's a lot you can do with just single cell types, whether that's nerves, cartilage, corneas, bone, muscle etc, and we're only just starting to imagine what might be possible with this technology.
Scaling up is definitely still an issue. In principle you can get infinite amounts of induced stem cells, but the actual practicalities of doing that are still very much in the early days. Partly because if you just leave stem cells growing in the lab they very quickly cease to be stem cells, and either become tumour forming cells or differentiate by themselves into cell types you might not want instead of the desired ones. There is some evidence that even tiny amounts of stem cells may be medically useful, because they secrete chemical messengers called cytokines which attract other stem cells and promote growth and repair. But if we're talking regrowing a whole liver we probably need several billion cells, not just a few tens of thousand.
Obviously since only a very few patients have been treated with stem cells, and only very recently, we don't know about long-term side effects. So far the safety profile looks good, but we will only know it's really safe once the technology is mature enough to have been tried on millions of patients over the course of decades. The big thing that people are worried about is that implanted stem cells may give rise to tumours. So far it seems like induced stem cells have less risk of turning into cancer than embryonic stem cells, partly because they don't have the same proliferative capacity.
We also can't reverse ageing or grow new clone bodies. Again, it's looking sliiiightly more possible than it seemed a couple of decades ago, but at very least we would need a whole lot better understanding of how cells interact and combine to form tissues and organs than we currently have. Plus a better understanding of what ageing actually is, and it's probably a combination of many different processes. What's clear is that cell ageing, where cells shorten their chromosome telomeres and lose their capacity to divide, is only part of story of body ageing. (And we have no idea at all how to "transplant" someone's personality / memories / brain into a new body; this may never be possible, and if it does become possible it probably won't be because of stem cells)
I was really charmed by the enthusiastic response to my previous post in this quasi-series. So please do ask more of those excellent questions that you were asking before. I can provide more broken-down explanations or links to peer-reviewed sources, depending what level you're at.
![[identity profile]](https://www.dreamwidth.org/img/silk/identity/openid.png){kind=small}
Nerve regrowth
Date: 2014-09-26 04:00 pm (UTC)Re: Nerve regrowth
Date: 2014-09-26 04:19 pm (UTC)Re: Nerve regrowth
Date: 2014-09-26 05:01 pm (UTC)Liv: THANK YOU THIS IS GREAT I enormously enjoyed it as did the people curled up on my bed to whom I read things out.
(no subject)
Date: 2014-09-29 10:55 am (UTC)(no subject)
Date: 2014-09-26 04:38 pm (UTC)Do you know if there is likely to be any long-term potential for using any of these developments in the brain? I'm thinking of things like traumatic brain injuries and Alzheimer's, especially. I'm guessing that this would be a very long-term thing if so, given the complexity of the brain and so forth.
(Inevitably I am also now wondering whether any of this will lead to any kind of treatment for any of my illnesses! I'm guessing it would be a long, long way off if so, but it's nice to think it might become possible, at least for people a generation or two further on. :-) )
(no subject)
Date: 2014-09-26 05:04 pm (UTC)There is some brain stuff going on, especially relatively "simple" conditions like the Parkinson's Disease I described in my post. The problem with repairing brain injury and degeneration is that you can't really recapitulate the structural changes in the brain that will have happened as a result of experience. So even if you could use stem cells, it's unlikely that the person would get their memories and skills back. But you might be able to restore some functionality, and maybe make it easier for them to relearn whatever they lost due to the damage.
For your illnesses, probably not the root causes at least in the short term, in big part because we mostly don't know what the causes are! But for treating some of the long-term damage that results from repeated minor injury, stem cells could well be a good option. They're already useful for joint repair, so that does look promising.
(no subject)
Date: 2014-09-26 06:13 pm (UTC)(no subject)
Date: 2014-09-29 10:59 am (UTC)(no subject)
Date: 2014-09-26 09:00 pm (UTC)(no subject)
Date: 2014-10-05 11:58 am (UTC)(no subject)
Date: 2014-09-27 09:51 am (UTC)(no subject)
Date: 2014-10-05 11:59 am (UTC)(no subject)
Date: 2014-09-28 02:22 am (UTC)(no subject)
Date: 2014-10-05 12:00 pm (UTC)(no subject)
Date: 2014-09-28 09:43 am (UTC)I can sort of understand that you might be able to take a cell and tell it to undifferentiate, though it's awesome that it's actually possible.
The thing I've got a bit more trouble understanding is how you then get it to re-differentiate in the direction you want. I can just about imagine that a living liver will be full, amongst other things, of messenger molecules that tell nearby stem cells to become liver cells; or that an embryonic mouse skeleton might have regions with a high concentration of messengers conveying 'oh nearby totipotent cell, please specialise to be oligopotent with a speciality in bone-forming'; but do we understand that process enough to be able to synthesise the set of chemicals that mean 'become a bone-forming stem cell'?
(no subject)
Date: 2014-09-29 12:52 am (UTC)(no subject)
Date: 2014-09-29 11:12 am (UTC)The good news is that people had already started working on this stuff from when we had only embryonic stem cells available. And there was already quite a lot of information available from developmental biology about exactly which messenger molecules you need for which cell types.
It's very empirical, very trial-and-error, though. It also turns out some cell types are much easier than others. But I've seen recipes for reliably getting your stem cells to differentiate into particular cell types, which have about four - six not ridiculously complicated steps. It's like, grow with messenger molecule X for 1 week, then change to molecules Y and Z for 2 weeks, then when you see the intermediate cell stage start to form, reduce the oxygen concentration below 2% and apply a slowly oscillating magnetic field, select out the population that have differentiated successfully, and maintain them with hormone N. So, complicated, and you have to imagine years of work of painstakingly trying different combinations to get to that recipe, but perfectly feasible.
(no subject)
Date: 2014-10-01 08:42 pm (UTC)(no subject)
Date: 2014-10-05 12:06 pm (UTC)There's no issue of having to use foetal material, either from abortions or from artificially created foetuses. There's no issue of manipulating genes which might be passed on to another generation, so if you receive some genetically altered stem cells say to treat your arthritic knee, any children you might have will not be affected in any way by your having that treatment.
(no subject)
Date: 2014-10-05 01:04 pm (UTC)(no subject)
Date: 2014-10-06 07:19 pm (UTC)