Hypertext in the book of life
Jul. 10th, 2014 08:05 pm![[personal profile]](https://www.dreamwidth.org/img/silk/identity/user.png){kind=small}
livOr, what an interested lay person should know about epigenetics.
I've been promising a post about epigenetics for ages, because it's one of the most exciting things that's happened in my field in the past decade or so, and it seems like most non-biologists aren't aware of it very much.
Why is it so exciting? Well, to start with there's the older insights which led to the modern field of epigenetics: in a multicellular organism, all cells have exactly the same genome, by definition, but the cells differentiate to take on specialist structures and functions. So there must be something going on beyond (ἐπί, the Greek prefix epi) the sequence of bases forming genes and chromosomes. It turns out that something is that the cell makes a series of chemical marks on the DNA and associated proteins, which turn genes on and off. Those marks are often surprisingly long-lasting, they're not just a short-term response to circumstances, something genes can also do. So you can't take a skin cell and transplant it to the liver, its epigenetic marks make it a permanent skin cell.
It's much more recently that we started to understand that patterns of epigenetic marks don't just follow a set developmental program – they can change in response to external circumstances. And the really mind-blowing thing is that some of these changes can be inherited. This means that a female parent's life circumstances can cause measurable alterations in the genes of offspring and more distant descendants, and there's starting to be evidence for male-line transmission as well, at least in animals and probably in humans too.
The other thing that's cool about epigenetics is that we're getting to the point where we understand it well enough that we can directly manipulate the epigenetic marks. If you change epigenetics, you change the nature of the cell itself, just as much as by directly editing the gene sequence (which can be done but is massively technically difficult, and ethically questionable in humans.) Which is a possible approach for treating cancer, and that's the reason why I got into the epigenetics world, but there's an even more exciting application: we can make stem cells. We can do the thing which was regarded as paradigmatically impossible throughout the twentieth century, we can effectively reverse the direction of development. So it's become possible to take an adult's cells and turn them into the rare kind which, like the cells of an early embryo, have the potential to become any type of tissue, manipulate them more or less at will in the lab, and return them to the same person's body to repair injuries and grow new tissue. In the very last couple of years, this is actually starting to be a treatment for real humans with real diseases.
So how does it work?
I would generally argue that much of the biochemical detail isn't important to know unless you're actually a molecular biologist. I'm going try to give a rough outline, if only to make my descriptions less abstract. One thing that's important about this is informally we're used to thinking of "genes" and "DNA" as pretty much synonymous, and on a biochemical level this is a major simplification. In human cells the actual DNA is in the form of chromatin, so the DNA is wrapped round protein "beads" called histones, and the string of beads is coiled and folded into a compact shape, to a greater or lesser extent depending on the region of the chromosome and the circumstances.
And the whole structure is covered in enzymes which are involved in carrying out the instructions encoded in the DNA sequence. There's a whole fairly complex protein machinery which actually does job of transcribing the DNA to RNA, allowing the gene to be expressed when the RNA does its job in the cell or gets translated into protein which likewise carries out cellular functions. Genes which don't get expressed are inactive; from the point of view of cell structure and function, they might as well not be there, because they're just sequences of DNA that don't do anything. I suppose metaphorically you can see the DNA as an instruction book; if nobody reads the book or carries out the instructions then the instructions themselves don't have any effect, they're just marks on paper.
The key point is that the transcription machinery and the structural proteins of the chromatin occupy the same physical space. So if the DNA is tightly wrapped round its histones and the string of beads coiled up tightly, there's no room for the transcription machinery to get in and the gene remains inactive. The histones and DNA can be modified chemically, changing the relationship of positive and negative charges, so that they repel eachother and the structure partly uncoils. Genes in "open" chromatin regions can potentially be expressed, but will only in fact be expressed if it's appropriate for the cell at that particular moment, because the transcription machinery itself is activated or inactivated by the appropriate combination of signals from inside and outside the cell. The patterns of chemical labels on the chromatin, and thus its open or closed state, can be copied when the DNA is copied, and some of this pattern is retained when gametes are formed and can therefore be passed on to offspring.
Isn't this kind of Lamarckian?
In some ways, yes. In case you're not aware, Lamarck was a nineteenth century scientist who proposed a theory of evolution which was superseded by Darwin's. His idea was that organisms would behave in ways that altered their bodies, and these changes would get passed on to their offspring. I don't know if Lamarck actually said this, but the typical illustration usually given is of the ancestor of the giraffe stretching higher and higher to reach leaves, lengthening its neck and passing on that advantage to its offspring. I want to make clear that Lamarck was not an idiot; Darwin also didn't propose a mechanism by which traits could be inherited, he was just lucky that the genetics discovered decades after he wrote happened to fit exactly with his theory of evolution. The other thing that happened to Lamarck was that Stalin decided that Lamarckian evolution was a better fit for Soviet ideology than Darwinism, and promoted the work of a not really trained horticulturist called Lysenko, who believed that alterations farmers made to plants would be heritable. And, being Stalin, forced everyone to follow Lysenko's wrong ideas and punished everyone who showed any contrary evidence. So Lamarckianism has become associated with the scientific process being corrupted for political ends, and contributing to mass starvation.
So you can imagine that any suggestion that acquired, rather than genetic, characteristics might be heritable met with massive resistance from the scientific community! However, there is more and more evidence accumulating that certain external events in the life of an organism lead to changes in the epigenetic marks, and that these marks can be passed on to offspring.
There's a classic natural experiment in the form of the partition of Germany after WW2: the populations of East Germany and the Bundesrepublik were pretty much genetically homogeneous before partition. In the years after the war, people in West Germany generally had much better diets than those in the Soviet East. The grandchildren and great-grandchildren of people who were pregnant during this era, born since reunification, have different epigenetic marks even though they have pretty much the same genes and nowadays the same lifestyle. As a result of expressing different genes, people with East German ancestry are going to have different physical bodies, different metabolism, different propensity to diseases etc, from people with West German ancestry, because their grandmothers experienced prolonged periods of inadequate nutrition before their mothers were born.
Some skeptics have tried to propose a more respectably Darwinian mechanism for this sort of phenomenon. For example, I don't think it's been completely ruled out that maybe the starving ancestors had some sort of altered womb environment as a result, and random genetic variation meant that some foetuses were able to survive in that altered womb environment. Just coincidentally, the genetic trait that promoted survival happened to correlate with a different epigenetic pattern. Selection against the foetuses that weren't fit to survive in the womb of someone who wasn't adequately nourished changed the overall frequency of which epigenetic patterns showed up in the next generation, enough to make a measurable change in the population.
In my view, the two possibilities are very nearly functionally equivalent. It's pretty clear that events during someone's lifetime can change epigenetic marks; we know smoking does, for example, and there's overwhelming evidence that trauma can change the epigenetics and therefore the gene expression of neurones in the brain. It's probable that other, less extreme experiences also change brain epigenetics, just as part of the normal neurological process of learning, it's just that trauma has such big effects it's more amenable to research. We also know that some epigenetic marks can be passed on; for example, the fact that ligers (with male lion fathers and female tiger mothers) are different from tigons (the offspring of crossing a lioness mother with a male tiger father) is incontrovertibly due to epigenetic differences known as imprinting. So it would almost be more surprising if it were definitively proved that life events couldn't affect future generations' epigenetic heritage, than if the now generally accepted consensus on epigenetic phenomena is true.
The thing is that epigenetics perfectly well follows Darwinian rules, even if it seems conceptually Lamarckian. It's just one more way that genes and environment / experiences can interact. The chemical marks on chromatin aren't made by some magical agent that's outside normal biology, this is epigenetics, not paragenetics. The reason why certain patterns get applied to certain genes is ultimately determined by the DNA sequence, because the DNA itself encodes the enzymes which add or remove the chemical groups. And where the marks get included or omitted also depends on the DNA sequence. It's as if, to extend the instruction book metaphor, the instructions in the book said, if you are more than 6' tall, delete every fifth word in this book. If a tall person happened to use the book, the next person who read it would get a different set of instructions from if the book only passed through the hands of short people (or disobedient people who didn't follow the instructions!) There's nothing magical or mysterious about this.
I'm not putting a lot of references in this, because looking for detailed citations for every single statement was one of the big reasons it's taken me several years to get round to writing this since I first thought of it. But there was a lot of buzz about this paper by Dias & Ressler, published late last year, where they conditioned some mice to fear a particular smell, and then their offspring down to the second generation were born with fear of that same smell. The damn article is paywalled because the Nature group is like that, so I can't give you a detailed analysis. But it seems to have caught the popular imagination in terms of epigenetic trans-generational inheritance. It wasn't especially surprising to me, but I think what may be different about it from the literature in the last five years about inherited effects of trauma is that it goes some way to do experiments to rule out other possible interpretations of why fear of the smell might be inherited. Things like using IVF so that it can't be womb environment, having the pups brought up by non-conditioned mothers so it can't be maternal behaviour affecting the offspring.
We're getting closer and closer to a convergence between animal experiments and observation of humans. Animal work shows a detailed molecular mechanism for how trauma alters the epigenetics of the chromatin in neurones. Because the epigenetically altered neurones express and repress different genes for neurotransmitter receptors, the way those brains respond to stimuli will be different, and quite possibly the brain structure will end up different because brains are plastic. The trauma is also affecting the epigenetics of gametes, so the patterns can be inherited, so the offspring will also have altered brains and therefore altered behaviour. Obviously you don't want to do that kind of experiment on humans, but we do see changed brain epigenetics persisting for several generations after trauma, and it's probably caused by the same kind of mechanism.
I suppose the question I haven't answered is, how does the experience of trauma lead to these epigenetic changes? I can't answer that in a very specific way, but in general, it's a bit like what happens with hormones. If you undergo puberty or start taking exogenous hormones, the chemicals are carried in your blood to the tissues that should be changing under the influence of sex hormones. Those cells will have receptors, proteins which recognize and bind to the hormones. The hormones will activate the receptors and the receptors in turn will activate some genes within the cell and deactivate others, so there might be genes for growing hair in appropriate places, or storing fat in certain parts of the body, or muscle growth, or whatever. Some of the cell factors affected by the hormones will be enzymes which can add or remove chemical marks from the chromatin, leading to permanent or at least long-term changes in gene expression. In the case of sex hormones, the epigenetic changes are not inherited, but it's equally likely that trauma could cause signalling molecules to tell neurones in the brain to turn on or off genes for relevant receptors, and at the same time tell the gamete-producing cells to mark the same genes for an open or closed state.
OK, this post is ridiculously long, I will post it and do one on stem cells another day. Please do ask any questions, whether it's because I've assumed knowledge and explained things with too much jargon and technicalities, or because I've simplified and glossed over something and you want more detail or want to challenge me.
I've been promising a post about epigenetics for ages, because it's one of the most exciting things that's happened in my field in the past decade or so, and it seems like most non-biologists aren't aware of it very much.
Why is it so exciting? Well, to start with there's the older insights which led to the modern field of epigenetics: in a multicellular organism, all cells have exactly the same genome, by definition, but the cells differentiate to take on specialist structures and functions. So there must be something going on beyond (ἐπί, the Greek prefix epi) the sequence of bases forming genes and chromosomes. It turns out that something is that the cell makes a series of chemical marks on the DNA and associated proteins, which turn genes on and off. Those marks are often surprisingly long-lasting, they're not just a short-term response to circumstances, something genes can also do. So you can't take a skin cell and transplant it to the liver, its epigenetic marks make it a permanent skin cell.
It's much more recently that we started to understand that patterns of epigenetic marks don't just follow a set developmental program – they can change in response to external circumstances. And the really mind-blowing thing is that some of these changes can be inherited. This means that a female parent's life circumstances can cause measurable alterations in the genes of offspring and more distant descendants, and there's starting to be evidence for male-line transmission as well, at least in animals and probably in humans too.
The other thing that's cool about epigenetics is that we're getting to the point where we understand it well enough that we can directly manipulate the epigenetic marks. If you change epigenetics, you change the nature of the cell itself, just as much as by directly editing the gene sequence (which can be done but is massively technically difficult, and ethically questionable in humans.) Which is a possible approach for treating cancer, and that's the reason why I got into the epigenetics world, but there's an even more exciting application: we can make stem cells. We can do the thing which was regarded as paradigmatically impossible throughout the twentieth century, we can effectively reverse the direction of development. So it's become possible to take an adult's cells and turn them into the rare kind which, like the cells of an early embryo, have the potential to become any type of tissue, manipulate them more or less at will in the lab, and return them to the same person's body to repair injuries and grow new tissue. In the very last couple of years, this is actually starting to be a treatment for real humans with real diseases.
So how does it work?
I would generally argue that much of the biochemical detail isn't important to know unless you're actually a molecular biologist. I'm going try to give a rough outline, if only to make my descriptions less abstract. One thing that's important about this is informally we're used to thinking of "genes" and "DNA" as pretty much synonymous, and on a biochemical level this is a major simplification. In human cells the actual DNA is in the form of chromatin, so the DNA is wrapped round protein "beads" called histones, and the string of beads is coiled and folded into a compact shape, to a greater or lesser extent depending on the region of the chromosome and the circumstances.
And the whole structure is covered in enzymes which are involved in carrying out the instructions encoded in the DNA sequence. There's a whole fairly complex protein machinery which actually does job of transcribing the DNA to RNA, allowing the gene to be expressed when the RNA does its job in the cell or gets translated into protein which likewise carries out cellular functions. Genes which don't get expressed are inactive; from the point of view of cell structure and function, they might as well not be there, because they're just sequences of DNA that don't do anything. I suppose metaphorically you can see the DNA as an instruction book; if nobody reads the book or carries out the instructions then the instructions themselves don't have any effect, they're just marks on paper.
The key point is that the transcription machinery and the structural proteins of the chromatin occupy the same physical space. So if the DNA is tightly wrapped round its histones and the string of beads coiled up tightly, there's no room for the transcription machinery to get in and the gene remains inactive. The histones and DNA can be modified chemically, changing the relationship of positive and negative charges, so that they repel eachother and the structure partly uncoils. Genes in "open" chromatin regions can potentially be expressed, but will only in fact be expressed if it's appropriate for the cell at that particular moment, because the transcription machinery itself is activated or inactivated by the appropriate combination of signals from inside and outside the cell. The patterns of chemical labels on the chromatin, and thus its open or closed state, can be copied when the DNA is copied, and some of this pattern is retained when gametes are formed and can therefore be passed on to offspring.
Isn't this kind of Lamarckian?
In some ways, yes. In case you're not aware, Lamarck was a nineteenth century scientist who proposed a theory of evolution which was superseded by Darwin's. His idea was that organisms would behave in ways that altered their bodies, and these changes would get passed on to their offspring. I don't know if Lamarck actually said this, but the typical illustration usually given is of the ancestor of the giraffe stretching higher and higher to reach leaves, lengthening its neck and passing on that advantage to its offspring. I want to make clear that Lamarck was not an idiot; Darwin also didn't propose a mechanism by which traits could be inherited, he was just lucky that the genetics discovered decades after he wrote happened to fit exactly with his theory of evolution. The other thing that happened to Lamarck was that Stalin decided that Lamarckian evolution was a better fit for Soviet ideology than Darwinism, and promoted the work of a not really trained horticulturist called Lysenko, who believed that alterations farmers made to plants would be heritable. And, being Stalin, forced everyone to follow Lysenko's wrong ideas and punished everyone who showed any contrary evidence. So Lamarckianism has become associated with the scientific process being corrupted for political ends, and contributing to mass starvation.
So you can imagine that any suggestion that acquired, rather than genetic, characteristics might be heritable met with massive resistance from the scientific community! However, there is more and more evidence accumulating that certain external events in the life of an organism lead to changes in the epigenetic marks, and that these marks can be passed on to offspring.
There's a classic natural experiment in the form of the partition of Germany after WW2: the populations of East Germany and the Bundesrepublik were pretty much genetically homogeneous before partition. In the years after the war, people in West Germany generally had much better diets than those in the Soviet East. The grandchildren and great-grandchildren of people who were pregnant during this era, born since reunification, have different epigenetic marks even though they have pretty much the same genes and nowadays the same lifestyle. As a result of expressing different genes, people with East German ancestry are going to have different physical bodies, different metabolism, different propensity to diseases etc, from people with West German ancestry, because their grandmothers experienced prolonged periods of inadequate nutrition before their mothers were born.
Some skeptics have tried to propose a more respectably Darwinian mechanism for this sort of phenomenon. For example, I don't think it's been completely ruled out that maybe the starving ancestors had some sort of altered womb environment as a result, and random genetic variation meant that some foetuses were able to survive in that altered womb environment. Just coincidentally, the genetic trait that promoted survival happened to correlate with a different epigenetic pattern. Selection against the foetuses that weren't fit to survive in the womb of someone who wasn't adequately nourished changed the overall frequency of which epigenetic patterns showed up in the next generation, enough to make a measurable change in the population.
In my view, the two possibilities are very nearly functionally equivalent. It's pretty clear that events during someone's lifetime can change epigenetic marks; we know smoking does, for example, and there's overwhelming evidence that trauma can change the epigenetics and therefore the gene expression of neurones in the brain. It's probable that other, less extreme experiences also change brain epigenetics, just as part of the normal neurological process of learning, it's just that trauma has such big effects it's more amenable to research. We also know that some epigenetic marks can be passed on; for example, the fact that ligers (with male lion fathers and female tiger mothers) are different from tigons (the offspring of crossing a lioness mother with a male tiger father) is incontrovertibly due to epigenetic differences known as imprinting. So it would almost be more surprising if it were definitively proved that life events couldn't affect future generations' epigenetic heritage, than if the now generally accepted consensus on epigenetic phenomena is true.
The thing is that epigenetics perfectly well follows Darwinian rules, even if it seems conceptually Lamarckian. It's just one more way that genes and environment / experiences can interact. The chemical marks on chromatin aren't made by some magical agent that's outside normal biology, this is epigenetics, not paragenetics. The reason why certain patterns get applied to certain genes is ultimately determined by the DNA sequence, because the DNA itself encodes the enzymes which add or remove the chemical groups. And where the marks get included or omitted also depends on the DNA sequence. It's as if, to extend the instruction book metaphor, the instructions in the book said, if you are more than 6' tall, delete every fifth word in this book. If a tall person happened to use the book, the next person who read it would get a different set of instructions from if the book only passed through the hands of short people (or disobedient people who didn't follow the instructions!) There's nothing magical or mysterious about this.
I'm not putting a lot of references in this, because looking for detailed citations for every single statement was one of the big reasons it's taken me several years to get round to writing this since I first thought of it. But there was a lot of buzz about this paper by Dias & Ressler, published late last year, where they conditioned some mice to fear a particular smell, and then their offspring down to the second generation were born with fear of that same smell. The damn article is paywalled because the Nature group is like that, so I can't give you a detailed analysis. But it seems to have caught the popular imagination in terms of epigenetic trans-generational inheritance. It wasn't especially surprising to me, but I think what may be different about it from the literature in the last five years about inherited effects of trauma is that it goes some way to do experiments to rule out other possible interpretations of why fear of the smell might be inherited. Things like using IVF so that it can't be womb environment, having the pups brought up by non-conditioned mothers so it can't be maternal behaviour affecting the offspring.
We're getting closer and closer to a convergence between animal experiments and observation of humans. Animal work shows a detailed molecular mechanism for how trauma alters the epigenetics of the chromatin in neurones. Because the epigenetically altered neurones express and repress different genes for neurotransmitter receptors, the way those brains respond to stimuli will be different, and quite possibly the brain structure will end up different because brains are plastic. The trauma is also affecting the epigenetics of gametes, so the patterns can be inherited, so the offspring will also have altered brains and therefore altered behaviour. Obviously you don't want to do that kind of experiment on humans, but we do see changed brain epigenetics persisting for several generations after trauma, and it's probably caused by the same kind of mechanism.
I suppose the question I haven't answered is, how does the experience of trauma lead to these epigenetic changes? I can't answer that in a very specific way, but in general, it's a bit like what happens with hormones. If you undergo puberty or start taking exogenous hormones, the chemicals are carried in your blood to the tissues that should be changing under the influence of sex hormones. Those cells will have receptors, proteins which recognize and bind to the hormones. The hormones will activate the receptors and the receptors in turn will activate some genes within the cell and deactivate others, so there might be genes for growing hair in appropriate places, or storing fat in certain parts of the body, or muscle growth, or whatever. Some of the cell factors affected by the hormones will be enzymes which can add or remove chemical marks from the chromatin, leading to permanent or at least long-term changes in gene expression. In the case of sex hormones, the epigenetic changes are not inherited, but it's equally likely that trauma could cause signalling molecules to tell neurones in the brain to turn on or off genes for relevant receptors, and at the same time tell the gamete-producing cells to mark the same genes for an open or closed state.
OK, this post is ridiculously long, I will post it and do one on stem cells another day. Please do ask any questions, whether it's because I've assumed knowledge and explained things with too much jargon and technicalities, or because I've simplified and glossed over something and you want more detail or want to challenge me.
![[identity profile]](https://www.dreamwidth.org/img/silk/identity/openid.png){kind=small}
(no subject)
Date: 2014-07-10 07:41 pm (UTC)Thank you for this post!
(no subject)
Date: 2014-07-10 08:16 pm (UTC)Epigenetics directly: I'm not sure there's a huge advantage in turning on genes for the appropriate secondary sex characteristics by changing the epigenetic marks directly, compared to changing them by supplying hormones which already do that in the appropriate tissues. Also we're not quite at the stage where we can edit the epigenetics of individual genes; at the moment it's all a bit crude and global, we can edit everything that fits a particular pattern, but not really single genes. Plus I don't think we yet know exactly which genes are involved in all the characteristics we associate with gender.
(no subject)
Date: 2014-07-11 06:44 am (UTC)(no subject)
Date: 2014-07-10 08:26 pm (UTC)(no subject)
Date: 2014-07-10 08:51 pm (UTC)(no subject)
Date: 2014-07-10 08:56 pm (UTC)The first article I found when I Googled it (now knowing that "epigenetics" was the magic word to add to my search string) said it had something to do with how female lions can have litters with multiple fathers, so male lions have epigenetic markers encouraging their cubs to grow like crazy so they have an advantage over littermates with different fathers, but female lions epigenetically fight this so they all come out relatively normal. But tigers are more monogamous, so they don't do this (or defend against it), so ligons come out huge. Does that seem basically reasonable?
(no subject)
Date: 2014-07-11 10:22 am (UTC)(no subject)
Date: 2014-07-10 08:31 pm (UTC)(no subject)
Date: 2014-07-10 08:52 pm (UTC)(no subject)
Date: 2014-07-10 09:03 pm (UTC)(no subject)
Date: 2014-07-11 02:15 am (UTC)A quick question: Genes in "open" chromatin regions can potentially be expressed, but will only in fact be expressed if it's appropriate for the cell at that particular moment, because the transcription machinery itself is activated or inactivated by the appropriate combination of signals from inside and outside the cell...
...The reason why certain patterns get applied to certain genes is ultimately determined by the DNA sequence, because the DNA itself encodes the enzymes which add or remove the chemical groups. And where the marks get included or omitted also depends on the DNA sequence.
Okay, to make sure I'm clear, the DNA chromatin/histones already have the chemical markers that will decide when the gene is expressed (and this is because DNA indirectly codes for these markers), but it's the environment of the cell itself that leads to whether the gene is actually expressed? It sort of sounds like a mobius strip of gene expression - the DNA transcribes the markers that tell the DNA when to be transcribed. Could you tell me more (or at least point me in the right direction of some literature) about the "appropriate combination of signals"?
(no subject)
Date: 2014-07-11 11:09 am (UTC)Let me see if I can break it down a bit. Any particular stretch of chromatin has a long-term state because of the chemical markers that make it open or closed. Closed chromatin can't do much because few proteins can get in to the tightly coiled structure. (One exception is the proteins which are able to change the chemical markers, otherwise this repressed state would be literally permanent.) Open chromatin, meanwhile, has the DNA relatively exposed, so any enzymes can get at it. But by default, it's still just sitting there. When the cell situation indicates that it's time to express that gene, a bunch of new proteins come in and do things like unwind the DNA and separate the two strands so that the bases of the genetic code are exposed, and stitch together all the RNA bases (C, G, A or U depending on what matches the exposed sequence of DNA) to make a messenger molecule. Meanwhile the DNA codes for all these elements, the proteins that make the chemical marks, the proteins that receive signals from the outside world and switch genes on or off, the machinery that copies the DNA to RNA, etc.
Instruction book metaphor: closed DNA is like a locked room in the library. Most of the time, the books in that room are not going to get read. A book somewhere in the open part of the library explains where the key is kept. A person might well unlock the door of that room (resetting the chromatin to its open state) but still not choose to read a particular book or carry out the instructions in it (the gene is open, but inactive.)
Concrete example: imagine a cell inside an embryo. You're happy with the fact that the DNA of that cell contains instructions for everything the cell needs to grow and divide, right? Genes for forming the cell nucleus and membrane, genes for metabolising nutrients into energy and appropriate biochemicals to make more cells, genes for regulating the program of doubling in size and then dividing in two.
There are also genes / instructions for how to make enzymes which can leave chemical marks on the DNA. And some of those enzymes have the ability to "read" the DNA sequence, so they will make marks in appropriate places, determined by the sequence, and not just at random. So part of the DNA says: if you see the same sequence repeated half a million times, it's probably the remnants of a dead virus, so you don't really want to transcribe that. Put some marks on that section of the chromatin so that there's loads of opposite charged bits near eachother and everything coils up really tightly and no other proteins can get in.
Now, imagine a bit further on in the process, the embryo is starting to turn into a baby. The cell now has a specific job apart from just growing and and dividing. Let's suppose the cell ends up in what will become the mammary glands. Depending on its exact position in the embryo, it will receive a number of chemical signals controlling the enzymes which mark genes. These signals will say, close off all the genes for producing liver enzymes and conducting electrical signals through nerve cells and making muscles contract and growing nails and hair - we don't need any of those things here! Some signals will say, open up all the chromatin that contains genes needed in mammary glands. Now the cell will transcribe and express the genes for making branching ducts towards the nipples. But the cell doesn't want to actually start producing milk while it's still inside an unborn baby, so the genes for milk production are open, but currently inactive.
Now supposing the baby is born and turns out to be a girl. The girl grows up and goes through puberty. During puberty, levels of sex hormones like oestrogen rise. Those bind to molecules in the cell called receptors (which are of course also coded by the DNA sequence), and the receptor + hormone together are able to interact with the DNA and turn on genes for restarting mammary gland growth, so the ducts expand and branch as the breasts also lay down fat and increase in size. The oestrogen + receptor pair can't turn on the genes for, let's say increasing bone density or causing ovulation, because those genes are in closed chromatin regions so they are permanently inactive in the mammary glands. Whereas the same hormone in the bones and ovaries will be able to turn on those genes because in those types of cells, their chromatin regions have been marked as open during embryo development.
Years later, the woman becomes pregnant. Late in pregnancy, there's a big spike in prolactin production. That hormone (with its receptor) will turn on the specific genes for making milk proteins and storing sugars and fat which can be released into milk. The genes for milk production have been left open all along, the chromatin was marked as open in the embryo because the cell was fated to be a mammary gland cell. But they were never activated until the cell received a prolactin signal. Just as oestrogen can't make milk glands suddenly start constructing bone, prolactin can't make bone cells suddenly start producing milk, because the bone cells' chromatin is epigenetically marked with the milk production genes in a closed region.
Any better?
(no subject)
Date: 2014-07-11 04:01 pm (UTC)(no subject)
Date: 2014-07-12 07:54 am (UTC)(no subject)
Date: 2014-07-11 04:18 am (UTC)(no subject)
Date: 2014-07-11 12:12 pm (UTC)(no subject)
Date: 2014-07-11 06:46 am (UTC)(no subject)
Date: 2014-07-11 12:15 pm (UTC)(no subject)
Date: 2014-07-11 08:42 am (UTC)I had no idea they could make stem cells - that's really encouraging given that a lot of people have ethical issues with getting them from embryos.
(no subject)
Date: 2014-07-11 08:45 am (UTC)(no subject)
Date: 2014-07-11 12:18 pm (UTC)And you're right, there are ethical issues with embryo-derived stem cells, which I think is partly why this stuff isn't getting as much publicity as it might. People are a bit afraid of fanatical pro-lifers getting angry about anything that mentions "stem cells" even though the whole point of this iPSC tech is to avoid having to use dead babies.
(no subject)
Date: 2014-07-11 01:18 pm (UTC)(no subject)
Date: 2014-07-11 01:40 pm (UTC)(no subject)
Date: 2014-07-11 02:08 pm (UTC)But it's unfortunately easy for something to get a spectre as "bad", and people to assume that it must still be bad, even if the reason for it has gone away :(
It also reminds me, that I always wish people would write laws that express what they actually want (even for small things) because they're more useful and less harmful if every subconscious assumption of the original drafters aren't eternally true, alas.
(no subject)
Date: 2014-07-11 11:46 am (UTC)So they key news, which I feel should have been trumpeted about at some point, but I obvious didn't see it in the mix of fake-excitement pop-sci news, are:
1. DNA has annotations on to say which bits are active. And some of these are fairly permanent, like to say "this cell is a liver cell". And some of these are passed on through gametes to offspring. In a way which many people thought sounded suspicious because it was lamarkian, but it's actually perfectly sensible, people knew it could happen in theory, but they hadn't realised how important it could be?
2. We didn't used to be able to grow liver cells from skin cells, we had to grow them from stem cells (which are cells which haven't differentiated into specialised sorts yet, as in a foetus). But now we can make stem cells out of skin cells?
(no subject)
Date: 2014-07-11 12:27 pm (UTC)I think there's a combination of reasons for why this isn't making a huge splash in popular media. Point 1 I think happened kind of gradually. Like, we always knew there were chemical annotations on DNA, and it only gradually became clear in the past 5-10 years just how important these are, as well as the cross-generational aspect. And yes, partly because of suspicions of Lamarckian thought, nobody wanted to be the person who became famous for "discovering" a debunked 19th century theory.
And point 2, yes, we can make stem cells out of skin cells. (Other cells may be somewhat better to use for technical reasons, but in principle, any cells.) I think this did get a bit of a splash when Yamanaka won the Nobel prize for this stuff in 2012, but even then, the pace at which this scientific discovery has turned into actual medical tech has been really fast. So the opposite problem to the gradual discovery of epigenetics, I don't think anyone really appreciated just how revolutionary Yamanaka's 2007 work was going to be.
I think it did get drowned out partly by fake excitement news, but also by people shouting about how stem cells are evil, because most religious fundamentalists really don't understand the crucial difference between embryonic and induced stem cells.
(no subject)
Date: 2014-07-11 02:04 pm (UTC)And yes, that makes sense. I think it's almost normal that actual discoveries find it hard to make it into the popular consciousness, either because there's no moment of revelation when they're incredibly revolutionary, or they blend into the background of "X might cure cancer (in twenty years maybe for some specific sorts of cancer)" that even good science reporting is prone to.
(no subject)
Date: 2014-07-12 06:25 am (UTC)(no subject)
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Date: 2014-07-17 12:57 pm (UTC)epigenetics is a word that i've been hearing for a while now, so that it's in my passive vocabulary and through exposure it acquired the feeling of a word that you know what it means, even though I didn't know anything beyond "a sub field of genetics". one of those words that was too familiar to look up or realise that i had no idea what it was! but now that i know, i think it is very cool.
I think in some ways I am in the same boat as you, being a liberal in liberal circles with still having some conservative views. For example, I do believe that life begins at conception (but I think abortion should be legal because it's the least worst solution at the moment once things get to the point that one is being considered.)
Epigenetics scares me to some extent because of the possibility for eugenics. I think gene therapy is good for treating the stuff that nobody wants to have: cancer, brittle bone, etc. but I worry that it will also be used to treat the parts of people that make them themselves, and about the dividing line between differences that are diversity to be celebrated and differences that are treatable.
There are things like autism where some people who have it want to be cured and others do not. Or it might turn out that homosexuality could be cured with gene therapy -- many of us find the very idea offensive but I'm sure some would take a cure if they could.
Stem cells
Date: 2014-07-12 09:34 pm (UTC)In order for stem cells to be as medically useful as possible, I would assume it is also necessary to rebuild the telomere to its initial length. Is that the case, and if so, does that happen automatically as a result of opening all the closed areas of the chromatin?
Re: Stem cells
Date: 2014-07-13 04:02 pm (UTC)I can exactly see why telomere manipulation might seem like a good idea, but right now it's not what we're doing. Because the goal is not to make cells exactly like true embryonic stem cells, the goal is to make cells which can be directed to form tissues which are needed to correct disease or repair injury. So there isn't any need to provide cells capable of dividing dozens of times, as embryonic cells can. What you want is stem cells which differentiate into, say, bone, cartilage and tendons to repair injury or reverse the effects of osteoarthritis. And once that's happened, you specifically don't want the cells to divide any more, you want them to carry on being mature bone, cartilage or connective tissue forming cells. Having a long telomere isn't an advantage; indeed evidence from experiments back in the 90s when people thought telomeres might be the key to eternal youth suggests that relengthening telomeres increases the risk that your introduced cells will create tumours.
Re: Stem cells
Date: 2014-08-05 11:48 am (UTC)The idea that reducing telomere length with cell division might act to reduce cancer risk is one I had heard of before, but I gather that cancer cells can restore the telomere indefinitely, so I wondered whether the extra risk of one restoration would be unreasonably large. Apparently it is.
Maybe eventually the right solution, if it is ever possible, would be to compare the DNA of multiple cells, probably using some modified bit of cellular machinery to do this, and correct some of the errors. Maybe that would allow telomere reconstruction not to cause significant cancer risk. Or not, maybe the cellular machinery becomes faulty and would need a separate rebuilding for that to work.
The best of my understanding at present is that shortening of telomeres is a cause of at least some of the the unpleasant effects of old age, and personally, I definitely feel like I could benefit from a rebuild from molecular level on up. If it ever becomes possible, I will be long gone, so purely a thought experiment.
Would I be right in surmising that, as far as we can tell so far, lengthening telomeres would be a necessary, but far from sufficient (and from what you say, conuterproductive on its own), step towards much longer healthy life?
(no subject)
Date: 2014-07-13 05:04 pm (UTC)This is all very very interesting stuff :)
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Date: 2014-07-16 01:04 pm (UTC)