경대리아 [889869] · MS 2019

2019-05-16 04:36:57
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[STUDENT:] So if it was just one hemisphere of the brain that became mutated, does that mean during development in the womb, that the two halves of the brain developed differently?

[DR. WALSH:] Well, the brain starts out as a single tube, actually, a hollow tube with fluid in the middle. And then the brain structure develops sort of as a lining of the tube. And then in the very front end of the brain that forms our cerebral cortex, that tube gets sort of branched almost in a Y fashion. And so the two hemispheres of the cerebral cortex get set aside relatively early on. And so that’s how mutations seem to be able to get mostly localized in one half of the brain and not the other. And of course, we don’t know that there’s not a single cell in that other hemisphere that has the mutation in it. Maybe there’s a couple on that side. We don’t formally know that. We just know that it’s not in his blood, but it is in his brain. Yeah.

[STUDENT:] Would there be any connection between hemimegalencephaly and an association with cancer?

[DR. WALSH:] So this is an example that I mentioned in the introduction where the AKT3 gene in other cell types, or actually other AKT genes— there’s a family of them—seem like they can become hyperactivated in cells that keep dividing. And it promotes them to keep dividing, and that can contribute to cancer. But in the brain, as I say, even though the gene is hyperactive, nonetheless, the

brain still has powerful mechanisms to force cells to stop dividing. And so the gene is still hyperactive even in the post-mitotic cells and seems to mess them up in different ways. And that’s where, without the ability to determine these genes, we wouldn’t have realized that a similar gene or the same gene is doing similar things but in totally different contexts. Yes, in the back there.

[STUDENT:] Would Dante have problems not only with fine motor skills, but with other things associated with the right side of the brain, such as creativity?

[DR. WALSH:] That’s a great question, and he certainly would have. And we don’t know, then, how much those activities can get taken over by his remaining left hemisphere. We know, for example, his left leg is ordinarily governed by the right hemisphere that’s removed, but he can walk. And so somehow, the remaining left hemisphere has learned to coordinate the left side of the body. And so some of his other activities are probably taken over by the left hemisphere as well. Hi, the woman there in the red shirt.

[STUDENT:] Knowing the genetic basis for hemimegalencephaly, what is the risk for it being inherited, like an inherited disorder?

[DR. WALSH:] So hemimegalencephaly is a genetic disorder, but it doesn’t seem to be inherited because it doesn’t, … because you can only inherit things it they’re passed through the germ cells, if you have a mutation that gets into the sperm or gets into the eggs. And in his case, it looks like the mutation is present only in brain cells. And so the mutation actually occurred after the germ cells were set aside from the brain cells. So this never runs in families and seems not to be an inherited condition, although it is a genetic condition. And that’s another irony that we’ve learned, you know, relatively recently, that so many diseases that are not inherited still reflect the abnormal sequences of genes. Yeah.

[STUDENT:] Did you have any ethical concerns with removing one hemisphere of Dante’s brain?

[DR. WALSH:] Oh, well, obviously you can imagine that the idea of a radical surgery like this is something that families have to grapple with, and every family has their own feeling about it. And you know, even doctors are like, holy cow, you know. But the surgery has been around for probably 15 or 20 years and is being used more frequently rather than less frequently, because it just seems, as desperate as it is, it just seems like the best way out of a very tough situation. Yeah.

[STUDENT:] Has there been any like, artificial protein regulators that people are studying so that it can act like a competitive inhibition to prevent the hyperactive cells from actively engaging in mitosis?

[DR. WALSH:] Well, so that’s a great question. So this particular AKT3 is a gene against which, in the cancer field, medicines have been developed that actually damp down that pathway in the context of cancer. And so we’re actually optimistic that some of those drugs might help kids that have this condition. We don’t know if it’s going to spare them the surgery or not. But it’s something that at least we’re now looking at ways to try.

I wish I could take more questions, but I think I’ll have to move on at this point. I’ve told you about a developmental disorder where the brain fails to achieve its normal size and ends up too big because it gets too much of a push when the stem cells are dividing. And I just want to return to this slide that shows, that illustrates that these tremendous genetic tools have allowed many labs to understand a lot of these developmental disorders over the last several years. And in the second half of the talk, I’ll tell you about a different disorder, a complementary disorder. I’ll tell you a little bit more about disorders where the brain ends up too small, and that’s a condition known as microcephaly. And that’s illustrated by the small brains in the lower left corner and in the middle of the left where I put that box around it. I mentioned microcephaly briefly. It’s defined as a small head, actually. That’s why if any of you remember when you went to your pediatrician’s office, they put a tape measure right around your head as though they were measuring you for a hat. What they’re actually doing is they’re measuring your brain because our head is basically a carrying case for our brain. That’s the way we brain-centric neurologists like to think about it. And in fact, you can get a pretty good idea of how big a kid’s brain is by just putting a tape measure around the outside of their head.

And so this is a genetic condition. There are many different genes that cause it. And so that is what sometimes makes it a little difficult to find any one of the genes because there are so many different genes that can cause this condition. As you might imagine, with the brain being small, these children are lacking many of the neurons that they would normally have. And so they typically show intellectual disability. They don’t usually have seizures. Even though they don’t have enough neurons, the neurons that they have look like they work pretty well, so kids can typically learn to walk. They’ll have limited language. But they’ll be, as I said, somewhat limited in their cognitive capabilities. So most forms of microcephaly are not dominant mutations. They’re, in fact, recessive mutations, where you only get the disease if you disable both of the two copies of the gene that you carry, because we carry two copies of most of our genes that are on our autosomal chromosomes. And so these conditions are usually not spontaneous. They’re in fact usually inherited. And usually, the mutations occurred hundreds or thousands of years ago and are carried in a silent way in the population. And when two people who unknowingly carry the same recessive mutation have children together, they will have affected children.

And so this shows two families that had children with microcephaly: one from Mexico on the left and one from Turkey on the right. And I have a little dot inside of the square that represents the father, and I have a little dot inside the circle that represents the mother, indicating that we think that they were silent carriers of a recessive mutation. And then they were normal themselves but had the bad fortune to have three affected children. And this is, you know, a recessive condition; usually one out of four children are affected. But unfortunately, the statistics were very unkind to this particular family. But that’s what brought them to research.

And then another family from Turkey had a similar family structure. There are some normal siblings that are not illustrated for simplicity. And since the family from Mexico is from a rural area, we thought there was a good chance that they might actually share a distant common ancestor and that they might actually be silently carrying not only a recessive mutation, but the same recessive mutation in

the gene, and that the children would then be homozygous for two copies of the exact same mutation. And we thought the same might be true of the family from rural Turkey as well.

And so we set about trying to find this gene about 15 years ago. And the way we did that at that time was to do genetic mapping to localize the gene. The way you do that is by using markers to find your way. We basically had at that time a good map of the genome. And that map has gotten better, and so actually, I’ll illustrate some data from this family that was done in the early 2000s using markers, where we had 500,000 different markers across the genome. And by marker, I just mean that there are sequences of the genome that tend to vary between different people, so they are usually heterozygous.

And so what we’re looking for is a part of the genome where it looks like the kids inherited the exact same thing from both parents and are homozygous. And so this shows some of the markers on the left: the father’s chromosome has an A and the mother’s chromosome has a C, so that’s different. Way on the right, you see that the father has a G, the mom has an A. That’s different. But in the middle, the markers—even though usually people have different versions, there, the mom and the dad chromosomes are exactly the same. And so we found blocks of the genome that were homozygous that looked like they could have been inherited from that common ancestor. And this is actually what the actual output of that marker analysis shows. This is actually a representation of those markers across just one chromosome. This happens to be chromosome number 19. One end is on the left, the Q arm is on the right, and the centromere would be somewhere around the middle. And the markers show up as either red or blue when they’re homozygous and yellow when they’re heterozygous. And so what we’re looking for are parts of the genome that lack yellow color and that have large blocks of homozygosity. And we can use a statistical model that allows us to recognize those blocks of homozygosity more easily. And that’s shown here in the purple, where purple represents homozygous and yellow represents heterozygous.

And so what we do in families like this is we look for the homozygosity. And we start with all of the chromosomes, two copies of all of them—except, of course, the X and the Y in males. And we can take an individual person and do that single nucleotide marker array to find the blocks of homozygosity. And when we did that in the Mexican family, we found that the first child had a variety of blocks of homozygosity throughout the genome from various sizes—some big, some small. And that made us think yes, indeed, it looks like the parents do have a distant common ancestor and that our mutation is probably going to be in one of those homozygous blocks, but it doesn’t really eliminate that much of the genome. It gets us down maybe about to 10% of the genome. But then when we look for the overlapping blocks that are shared by two affected siblings, then that narrows it down to a much smaller segment of the genome. And in fact, when we compare the homozygous segments in all three of the affected kids, that got us down to just one block of homozygosity in the entire genome. And this is where we were, actually, in 1998. We knew that the gene was right there on chromosome 19. But you can see it’s actually a substantial portion of chromosome 19. So we know that our gene is going to be one of the genes in that interval, and it’ll have a homozygous mutation.

But now, I’ll show you a blowup of that region. And in fact, even that little homozygous region that looks so small actually has 6 million base pairs of DNA in it. And in fact, there were over 150 genes in there. And so in the early 2000s, we sort of had taken the project this far, and it was really not realistic and not something we could even afford to do to set about sequencing all 150 of those genes one-by-one with the old-fashioned technology. And so basically, we set this project aside on the shelf for a few years and let that graph of DNA sequencing costs take a few turns until the sequencing got cheaper. And we came back to it in the second half of the first decade of the 2000s because that’s when the next-generation sequencing made this project suddenly very easy, because around 2008, the project was picked up again, because now we had fast and inexpensive sequencing that could jump-start this research. We could then use these next-generation sequencing technologies and take all of the genes, all of the DNA in that segment of chromosome 19 and sequence them all, and then also analyze them in very high-throughput ways, because so many genomes had been sequenced at that time.

So from that segment, we found that there were over 2,000 genetic variants, places where the affected children’s DNA sequence was different from the consensus human sequences that were available on the Internet. And in fact, we could also find by looking at the genomic sequences of lots of normal people who were on the Internet at that time—Craig Venter’s DNA sequence, Jim Watson’s DNA sequence—were available on the Internet. We could say how many of these variants were not present in any of these normal people whose DNA sequence was on the Internet. And we found that there were only about 300 of these variants that were never seen in normal people, and we assumed that normal people would never carry these variants. And so that actually starts narrowing us down to relatively fewer possible mutations. And then we could start looking at, well, what do the different mutations do. Which of the mutations actually are likely to matter? Which might actually change something about a protein by causing a stop codon that might disrupt the size of the protein or by changing one amino acid to another that might change the function of the protein?

And so only seven of these changes that we had identified were potentially likely to be deleterious to encoded proteins. And so this just summarizes how we can go through this targeted sequencing, going from a large number of potential variants to a relatively small number of candidate genes that are shared by the three siblings of the first family from Mexico, but now we did exactly the same process in the second family from Turkey. So this allows us, then, a second opportunity to look at the intersection of the potential mutations in the two families. And so Family A had seven candidate mutations in this chromosome 19 interval. Family B had four potential mutations in that same interval. And only one gene was mutated in both families, and that’s a gene called WDR62. So by a very rapid process, we were able to take a lot of information and siphon it very quickly and funnel it down and find a single candidate gene.

And in fact, once we had that gene, we and other labs quickly found 20 other families that had other mutations in the same gene. In fact, this gene was discovered simultaneously by three different labs who were all, … who had all been at the same place as us, stuck for five or more years looking for this gene because of the limitations of DNA sequencing, and then suddenly enabled. And so we were just waiting for the DNA sequencing to get better to find the gene.

So what does WDR62 actually do in the cell? We know that it regulates the size of the brain, and we know that regulating the size of the brain is really important. And so how does it actually function in the cells that make up the brain, because that’s really a lot of the biological interest of studying these disorders is also to tell us what it means about how the brain is formed. So we started analyzing where the protein is actually localized. And we found that it’s localized not in the neurons of the brain, but in the dividing cells of the brain. So it’s not a gene that functions in the neurons itself, but it’s a gene that functions in the stem cells, the dividing cells that give rise to those neurons. And WDR62 specifically localizes to the actual mitotic spindle of dividing cells. The left panel shows you what a mitotic cell looks like. And you’ve probably learned this in your biology textbooks. You can see that the actual spindle, the microtubules that make up the spindle, are outlined in red, because that’s an antibody that reacts with those spindle microtubules. You can see the blue shadows, which are the chromosomes, that are aligned along the middle of the spindle and just getting ready to be segregated. And then you can see the two ends of the spindle outlined in green, the centrosomes that organize the spindles. And we found that WDR62 is associated with these centrosomes of the mitotic spindle. In the right panel, now WDR62 is labeled in green. And you can see that that localized predominantly to the centrosomes at the outsides of the spindles. And in fact, WDR62 is not the first gene that had been identified to cause microcephaly. It was about the sixth or the seventh. And remarkably, many of these microcephaly proteins localize to the spindle.

Another microcephaly protein called ASPM, which I’ll tell you a bit more about in a few minutes, also localizes to the spindle, as do a half a dozen others. And so remarkably, it seems like there’s something very important about the spindle—and not the whole spindle, but just the centrosome, the organizing sites of the spindle—that seem to be very important for controlling brain size. And to tell you a bit more about how we think that works, I’ll tell you a little bit more about how the human brain develops by, if we can show this video that summarizes how the stem cells in the brain generate the cerebral cortex.

So this shows, then, a schematic movie through a fetus. And here is that developing cortex. The ventricle is the hollow, fluid-filled space. The cortex develops in the lining of that tube. And then if we look at a close-up, the fluid-filled space, the ventricle is down at the bottom, and that lining contains these neural stem cells that have these very elongated outer processes. They’re called radial neuroepithelial cells or radial glial cells. And they divide to form the post-mitotic cells, which are represented by those little bubbles that then look like they’re floating to the surface, because the post-mitotic, nondividing neurons actually migrate from the inner part of the brain to the outer part of the brain in what is actually a very complicated process all its own that we don’t have time to go into in detail.

So you can see the migrating cells going up. The first-born cells that first reach the cortex actually end up forming the bottom layer of the cortex. And the later-born neurons actually migrate past them. And so the last-born neurons of the cortex are always being added to the top, like layers of a cake. And so the very, very last-born neurons are in the very outermost part of the brain. The first-born neurons are now being shaded red. And those end up occupying the bottom of the brain. And so the longer these

stem cells divide, the greater the number of neurons that get added, and these last-born neurons tend to be added to the outermost part of the cortex.

And so looking again at these dividing cells, a variety of work from many labs suggests that exactly how those stem cells divide is very important in controlling how big the brain gets. When those cells are at an early stage of development, they tend to divide side-by-side with a horizontally oriented mitotic spindle to form two daughter cells that are also stem cells. So it’s stem cells generating stem cells, which grows the cell population exponentially. And that’s shown by that horizontal division on the left. A little bit later during development, the neurons start to be formed. And the neurons are post-mitotic. And so those cell divisions that generate the neurons or that generate one neuron tend to have a slightly different orientation. They divide to form one stem cell plus a post-mitotic cell. And so this actually results in a slower growth of the overall population because it’s linear growth rather than exponential growth. But eventually, in order to form neurons, you have to start having this linear phase. And these neuron-generating cell divisions tend to be oriented slightly differently and generate, as I said, post-mitotic cells. And so it looks like the orientation of that mitotic spindle is extremely important for the decisions that cells make about their fate. And the orientation of the spindle and other aspects of the centrosome that we don’t completely understand seem to control whether a cell takes on the fate of a dividing cell or whether a cell takes on the fate of a post-mitotic neuron.

And so experiments from a few different labs have shown that when you deplete a microcephaly gene called ASPM—and the same seems to be true for WDR62 as well, and other microcephaly genes—the mitotic spindle tends to turn a little bit. And it tends to turn to an angle where the cell divisions are more likely to generate post-mitotic cells. And this slight twist seems to have a very important consequence because by turning the mitotic spindle slightly, you form fewer stem cells and more post-mitotic cells. And so if you turn the spindle too early too often, you may form neurons at a stage earlier than you should and end up with a brain which is ultimately smaller than it should be. And so this mitotic spindle orientation seems to be very important to influence cell fate and cell proliferation.

So in the last few minutes, I’ll just tell you one unexpected aspect of this work that we think of as experiments in medical genetics and in developmental neuroscience. And it has to do with how the human brain evolved. The kids with microcephaly have a brain which is abnormally small, and people had long wondered whether some of the genes that, if they’re missing, make our brain end up being small might also have other sorts of ways in which they can differ from one species to another that might have helped make our brain big during earlier evolutionary time. So this figure here summarizes the brain size of humans way on the right, which is about 1,300 to 1,500 grams, compared to the brain size of our ancestors. And chimps have a brain size of about 400 grams. And then earlier human ancestors started at about 600 grams. And you can see how brain size progressively increased over the last several million years. And so this must represent some kind of genetic changes to something that allows the brain to get bigger but not suddenly, like Dante’s brain, and in an uncoordinated way like his brain, but in a gradual way that allows the new neurons to be properly integrated and properly functional.

And so it was long a hypothesis that genes that affect brain size might have also had this double evolutionary role. And so identifying some of the first microcephaly genes gave laboratories the chance to specifically address this hypothesis to see whether the microcephaly genes might play a role. And the way this sort of experiment is done is to take the same gene—ASPM or CEP63 or some of the other microcephaly genes that have these evolutionary roles—and sequence them in humans who have a brain size of about 1,300 or 1,400 grams, and then compare it to the DNA sequence in our closest existing relatives and see how similar they are. If the gene sequence is exactly the same in all of the different species, then you wouldn’t expect that it has any particular role in evolution. But a lot of genes are actually very highly conserved. But maybe the gene has more differences than you might expect, and that might suggest the gene actually plays a role in making those species different.

And so in fact, when that sort of analysis was done for ASPM and for one or two other microcephaly genes as well, there was an excess of differences in the gene, particularly in the lineage of beings that lead to humans, suggesting, and strongly suggesting, that these genes might have played an evolutionary role. And so this is remarkable because it gives us a way of thinking about how the evolution of our brain happened, which … you know, of actually thinking about how those genes acting over millennia might have actually worked in the cell biological way to make our brain bigger than that of other species. And it may come down to something like this control of cell fate and proliferation that something as simple as a little tweak in the angle of a mitotic spindle might allow a brain to become larger, but in a very organized way. And so if there’s a little bit of a turn of the mitotic spindle due to perhaps some subtle functional changes in microcephaly genes, that might allow these stem cells to divide just a couple more times in the human brain compared to the brain of other species. But what happens with those couple of extra cell divisions is that you’re adding a few new neurons to the top of the cortex, but you’re adding neurons that don’t exist anywhere else in nature. You’re adding something completely new. And then those new neurons have the ability to potentially take on functions that are not served by cortical neurons in other species.

So just to conclude, then, these structural abnormalities are an important cause of human disability. You don’t hear about them quite as often as autism or other … or intellectual disability because they’re individually quite rare and because the kids are often severely disabled. But we can learn a lot about them by understanding their genetic causes. And then finally, surprisingly, some of the genes that cause structural brain abnormalities were targets of brain evolution. They control the shape of our brains, and they allow our brain to be shaped differently and to do amazing, different things that the brain of other species can’t do. So why don’t I stop here and take questions on both parts of the talk? Yes, in the back.

[STUDENT:] How does the skull know to stop growing based on how big the brain is?

[DR. WALSH:] That’s a great question, and that’s a complete mystery. When the brain is first growing, the actual skull forms as plates. And the plates are connected by just soft tissue, and so they sort of float on top of the brain. And the plates start fusing together around the time of birth, and they don’t complete fusing until after birth. And so actually, when the baby is born, those plates actually scrunch a little bit and can even overlap to allow the baby to exit the birth canal. And we don’t know exactly

what matches the bones to the brain so perfectly. But obviously, it’s a problem. There are occasional conditions where that soft tissue starts turning to bone too soon, and the brain starts getting squeezed, and that can be a big problem, as you can imagine. Yeah.

[STUDENT:] So if megalencephaly can, like, develop during the developmental stages of pregnancy rather than be inherited, is the same true for microcephaly?

[DR. WALSH:] It can; … most of the causes of microcephaly look like they’re recessive, but there’s that one cause that’s associated with that deletion of the end of chromosome 1. And that—as far as we can tell, that’s always been present as a mutation in the germ line, meaning that it happened in a sperm or an egg. But I suppose it’s possible that it could happen as a somatic mutation, but we wouldn’t have detected it, because those kids don’t get surgery. So we can’t study their brain tissue, so we don’t really know.

[STUDENT:] I know this is a very controversial subject, but based on your research and on the evolutionary theory, do you believe that our genome, the size of our brain, or the structure of our neurons might play a role in intelligence?

[DR. WALSH:] Well, I don’t think that’s controversial. I don’t think anyone would disagree that the structure of our brain is important for determining intelligence. A lot of people ask, you know, are people with big brains smarter than people with small brains, you know, and Lord Byron had a brain of 2,000 grams, and Walt Whitman had a brain of 1,000 grams, and so people can argue who was the greater poet. We think that there’s a general relationship between brain size and intelligence, and studies have shown that. But it’s by no means absolute. And some people who have brains that are one or two standard deviations below normal can be absolutely as highly intelligent as anyone else. Thanks very much for your attention.




봐야할거 딲 1/4인대 이거 요약점 아 ㅋㅋ...하,,,,

0 XDK

  1. 유익한 글을 읽었다면 작성자에게 덕 코인을 선물하세요.

  • epoché · 863038 · 05/16 04:38 · MS 2018

    ㅁㅊ군 개토나오는디

  • 경대리아 · 889869 · 05/16 04:39 · MS 2019

    셍물교수님이 으대학부시라 학셍들한테 관심가져보라고 이런거 과제내심서 꼬드기는거가튼대 개노잼이에요,,, ^~^...

  • 호앵애앵앵 · 840588 · 05/16 05:02 · MS 2018

    저도 요약은 못하구요..오역있을 수는 있으나 어차피 밤샐거 번역은 해드릴 수 있어요...

    [STUDENT:] So if it was just one hemisphere of the brain that became mutated, does that mean during development in the womb, that the two halves of the brain developed differently?
    그럼 만일 뇌의 절반만이 변이되었다면, 그것이 자궁에서 발달할 시기에 뇌의 양쪽 절반이 다르게 발달했다는 것을 의미합니까?

    [DR. WALSH:] Well, the brain starts out as a single tube, actually, a hollow tube with fluid in the middle. And then the brain structure develops sort of as a lining of the tube. And then in the very front end of the brain that forms our cerebral cortex, that tube gets sort of branched almost in a Y fashion. And so the two hemispheres of the cerebral cortex get set aside relatively early on. And so that’s how mutations seem to be able to get mostly localized in one half of the brain and not the other. And of course, we don’t know that there’s not a single cell in that other hemisphere that has the mutation in it. Maybe there’s a couple on that side. We don’t formally know that. We just know that it’s not in his blood, but it is in his brain. Yeah.
    글쎄, 사실 뇌는 가운데가 액체로 찬 관으로 시작합니다. 그리고 뇌 structure는 관의 lining처럼 발달합니다. 대뇌겉질을 구성하는 뇌의 제일 앞 부분에서는 그 관이 y모양으로 갈라집니다. 그리고 대뇌겉질의 두 반구(뇌)는 비교적 빨리 분리됩니다. 그게 돌연변이가 뇌의 한 쪽 절반에 주로 분포하는 경향이 있는 듯한 이유입니다. 그리고 당연한 거지만, 우리는 그 돌연변이를 가진 세포가 다른 뇌 반쪽에 없다고 보장할 수는 없습니다. 좀 있을 수도 있겠죠, 우리는 그건 모르지만, 우리의 뇌에만 있는 것입니다(?)

    [STUDENT:] Would there be any connection between hemimegalencephaly and an association with cancer?
    편측거대뇌증과 암과도 연관이 있을까요?

    [DR. WALSH:] So this is an example that I mentioned in the introduction where the AKT3 gene in other cell types, or actually other AKT genes— there’s a family of them—seem like they can become hyperactivated in cells that keep dividing. And it promotes them to keep dividing, and that can contribute to cancer. But in the brain, as I say, even though the gene is hyperactive, nonetheless, the brain still has powerful mechanisms to force cells to stop dividing. And so the gene is still hyperactive even in the post-mitotic cells and seems to mess them up in different ways. And that’s where, without the ability to determine these genes, we wouldn’t have realized that a similar gene or the same gene is doing similar things but in totally different contexts. Yes, in the back there.
    이게 제가 개요에서 설명했던 예시인데, 다른 세포 유형들의 AKT3 유전자나 실제로 다른 AKT 유전자들이 - 그런 family가 있습니다 - 계속 분열하는 세포들에서 활발할 수 있는 것처럼 보이는 겁니다. 그리고 그것은 그 세포들을 계속 분열하도록 하는데, 그것이 암을 유발할 수는 있겠죠. 그러나 뇌에서는 유전자가 활발하더라도, 결과적으로, 뇌는 세포들이 분열을 멈추도록 할 수 있는 강력한 매커니즘이 있습니다. 그래서 그 유전자는 post-mitotic cells에서도 활발하고 그것들을 다양한 방법으로 망가뜨리는 듯 합니다. 그리고 그 시점에서, 그 유전자들을 규명할 능력 없이는, 우리는 비슷하거나 같은 유전자가 완전히 다른 맥락 속에서 비슷한 걸 한다는 걸 알아채지 못했을 겁니다.

    [STUDENT:] Would Dante have problems not only with fine motor skills, but with other things associated with the right side of the brain, such as creativity?
    Dante가 정교한 motor skills뿐만 아니라, 창의력과 같이 우뇌에 연관된 다른 것들에도 문제가 있을까요?

    [DR. WALSH:] That’s a great question, and he certainly would have. And we don’t know, then, how much those activities can get taken over by his remaining left hemisphere. We know, for example, his left leg is ordinarily governed by the right hemisphere that’s removed, but he can walk. And so somehow, the remaining left hemisphere has learned to coordinate the left side of the body. And so some of his other activities are probably taken over by the left hemisphere as well. Hi, the woman there in the red shirt.
    좋은 질문입니다. 그는 명백히 그럴 것입니다. 그리고 우리는 그의 좌뇌가 그 활동의 얼마만큼을 떠맡아 책임질(?) 수 있을지 모릅니다. 예시로, 우리는 지금은 제거된 그의 우뇌에 의해 그의 왼쪽 다리가 지배되는 걸 알지만, 그는 걸을 수 있습니다. 그리고 어떤 식으로, 남은 좌뇌는 좌반신을 조종하는 법을 배웠습니다. 그리고 몇몇 다른 활동들도 그의 좌뇌에 의해 taken over되었을 겁니다. 안녕하세요, 레드 셔츠의 여성분.(이거 강의록인가요...?)

  • 경대리아 · 889869 · 05/16 05:04 · MS 2019

    네 강의로 보긴 한시간짜리라 구찮아서 스크립트 내용만 떠듬떠듬 보는데 곶통스럽읍니다....ㅠㅠㅠ

  • 호앵애앵앵 · 840588 · 05/16 05:04 · MS 2018

    한시간 동안 쉬지않고 말하나 보네요...무슨.......전 일개 중졸이라 하나도 알아듣지 모탑니다....

  • 경대리아 · 889869 · 05/16 05:05 · MS 2019

    30분정도 보고 나서 뒤에 반 가져온게 이정도 양입니다 ㅠㅠ..

  • 경대리아 · 889869 · 05/16 05:07 · MS 2019

    그래도 해석 감사합니다 ㅎㅎ

  • 호앵애앵앵 · 840588 · 05/16 05:10 · MS 2018

    [STUDENT:] Knowing the genetic basis for hemimegalencephaly, what is the risk for it being inherited, like an inherited disorder?

    [DR. WALSH:] So hemimegalencephaly is a genetic disorder, but it doesn’t seem to be inherited because it doesn’t, … because you can only inherit things it they’re passed through the germ cells, if you have a mutation that gets into the sperm or gets into the eggs. And in his case, it looks like the mutation is present only in brain cells. And so the mutation actually occurred after the germ cells were set aside from the brain cells. So this never runs in families and seems not to be an inherited condition, although it is a genetic condition. And that’s another irony that we’ve learned, you know, relatively recently, that so many diseases that are not inherited still reflect the abnormal sequences of genes. Yeah.


    편측거대뇌증이 유전되면 위험?
    -세균 세포를 통해 전파되는 것들만 유전할 수 있기에 딱히 유전되는 것 같지는 않다
    -그의 케이스에서는, 돌연변이가 뇌세포엔만 있다
    -세균 세포가 뇌세포로부터 분리된?후에 돌연변이가 실제로 발생한 것임.
    -그래서 유전적인 거긴 하지만 가족이 물려받지는 않는다
    =우리가 배운 또다른 아이러니 ; 물려받지 않는 많은 병들도 유전자의 비정상적인 시퀀스를 가진다?

    [STUDENT:] Did you have any ethical concerns with removing one hemisphere of Dante’s brain?

    [DR. WALSH:] Oh, well, obviously you can imagine that the idea of a radical surgery like this is something that families have to grapple with, and every family has their own feeling about it. And you know, even doctors are like, holy cow, you know. But the surgery has been around for probably 15 or 20 years and is being used more frequently rather than less frequently, because it just seems, as desperate as it is, it just seems like the best way out of a very tough situation. Yeah.

    단테의 뇌 반구를 제거하는 것에 있어서 윤리적인 걱정은 없는가?
    -물론 이런 급진적인 수술은 가족들이 싸우는 것이고, 모든 가족은 각각의 입장 있다
    -의사들도 아이고 세상에 하는 것
    -그러나 이 수술은 15~20년 되었고 요즘은 꽤나 자주쓰이는데, 엄청나게 힘든 상황에서는 최선이기 때문이다.

  • 경대리아 · 889869 · 05/16 05:11 · MS 2019

  • 호앵애앵앵 · 840588 · 05/16 05:20 · MS 2018

    [STUDENT:] Has there been any like, artificial protein regulators that people are studying so that it can act like a competitive inhibition to prevent the hyperactive cells from actively engaging in mitosis?

    [DR. WALSH:] Well, so that’s a great question. So this particular AKT3 is a gene against which, in the cancer field, medicines have been developed that actually damp down that pathway in the context of cancer. And so we’re actually optimistic that some of those drugs might help kids that have this condition. We don’t know if it’s going to spare them the surgery or not. But it’s something that at least we’re now looking at ways to try.

    hyperactive한 세포들이 세포분열에 활발히 관여하는 것을 막는 역할로 작용되는, 사람들이 연구하는 인공적인 단백질 조정기가 있었는가?

    -AKT3은 암의 맥락에서 그 퇴로를 차단하는 치료약이 개발된 유전자
    -그런 약들이 이런 상태의 아이들을 도울 거라고 긍정적으로 봄
    -수술을 하지 않아도 될지는 모르겠으나 어쨌든 시도할 방법을 찾는 것임.

    I wish I could take more questions, but I think I’ll have to move on at this point. I’ve told you about a developmental disorder where the brain fails to achieve its normal size and ends up too big because it gets too much of a push when the stem cells are dividing. And I just want to return to this slide that shows, that illustrates that these tremendous genetic tools have allowed many labs to understand a lot of these developmental disorders over the last several years. And in the second half of the talk, I’ll tell you about a different disorder, a complementary disorder. I’ll tell you a little bit more about disorders where the brain ends up too small, and that’s a condition known as microcephaly. And that’s illustrated by the small brains in the lower left corner and in the middle of the left where I put that box around it. I mentioned microcephaly briefly. It’s defined as a small head, actually. That’s why if any of you remember when you went to your pediatrician’s office, they put a tape measure right around your head as though they were measuring you for a hat. What they’re actually doing is they’re measuring your brain because our head is basically a carrying case for our brain. That’s the way we brain-centric neurologists like to think about it. And in fact, you can get a pretty good idea of how big a kid’s brain is by just putting a tape measure around the outside of their head.

    줄기세포가 분열할때 push를 너무 받아서 뇌가 정상적인 크기를 벗어나 거대해지는 발달적 장애
    -이런 유전자적 도구들이 많은 랩에서 최근 몇 년동안 많은 발달장애를 이해하게 도와줌

    상호보완적인 장애 - 너무 작은 뇌(소뇌증)
    -소아과에서 머리둘레를 재는 이유 - 머리는 뇌의 보관 케이스니까.(우리같은 뇌신경학자들은 이렇게 생각하는 걸 좋아함)

    And so this is a genetic condition. There are many different genes that cause it. And so that is what sometimes makes it a little difficult to find any one of the genes because there are so many different genes that can cause this condition. As you might imagine, with the brain being small, these children are lacking many of the neurons that they would normally have. And so they typically show intellectual disability. They don’t usually have seizures. Even though they don’t have enough neurons, the neurons that they have look like they work pretty well, so kids can typically learn to walk. They’ll have limited language. But they’ll be, as I said, somewhat limited in their cognitive capabilities. So most forms of microcephaly are not dominant mutations. They’re, in fact, recessive mutations, where you only get the disease if you disable both of the two copies of the gene that you carry, because we carry two copies of most of our genes that are on our autosomal chromosomes. And so these conditions are usually not spontaneous. They’re in fact usually inherited. And usually, the mutations occurred hundreds or thousands of years ago and are carried in a silent way in the population. And when two people who unknowingly carry the same recessive mutation have children together, they will have affected children.

    그래서 이것은 유전적임. 많은 유전자들이 관여함=가끔은 너무 많아서 어떤 유전자를 찾기도 힘듦

    뇌가 작으면 뉴런 부족으로 지적 능력 떨어짐 / 발작은 없음 / 걸을 수는 있음 / 언어 한계는 인지적 한계
    소뇌증의 대부분은 지배적인 돌연변이가 아님. 오히려 열성의 돌연변이 - 두 유전자 모두 문제가 있어야 병에 걸림
    저절로 일어나지 않고 유전적임
    자기들도 모르는 채로 이런 열성의 돌연변이를 가지는 두 사람이 애를 만들면 애가 영향받는다

  • 경대리아 · 889869 · 05/16 05:22 · MS 2019

    감사합니다!!!!ㅎㅎ