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Milk Oligosaccharides - Structure and Function
Prof. Lars Bode, University of California San Diego, CA | USA
Wednesday, Sept. 25, 2019 · 8:05 a.m. · 54m 27s
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good morning and thank you very much for the invitation for putting this program together for an eye for hosting us
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we heard about all exact what's quite a bit the first two days
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the word popped up here and there michael why i'm pretty biological exact rights
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so this morning we gonna really died deep into what that
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means human note all exact words were short h. m. m.'s
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couple of other words but disclosures where the funding is coming from and then we go light in
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uh and i start with a statement that we've seen a few times in previous presentations at the first today
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and this is from the editorial commentary land suppressed feelings is
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twenty sixteen that said that the death of eight hundred twenty three
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thousand children and twenty thousand mothers each year could be averted
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through universal breastfeed along with economic savings of three hundred billion dollars
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and for us the question is why is that
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how does it work what is behind that statement what is inhuman not that makes it sort
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of so if we left the curtain behind the statement here and look what is a human
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one of the market molecules that we find him like this proteins fat
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like those ass predominant not sure and then there's all exact
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five to fifteen graham in module milk which often exceeds the amount of total protein
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and in comparison to bovine milk is a hundred to a thousand fold more that we find in one yep
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and since polemic is the basis for most infant formula there's hardly any human all
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got exactly it's in infants at least until beast gonna come back to that and that
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so the talks about structure in function and i'm gonna keep the structure part
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as short and uncomplicated as possible and we have to talk about a little bit
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so it's not as a dramatic us this picture shows when we think of sure we think of something like this
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when we think of sugar in the infant space we think of something like that's
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ah that's fairly complex to me already looking just at the structure
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but uh when we talk about human not all i guess i quite which are complex shoulders that's not the same
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so it's not the typical sure that you think of that you associate something bad with is actually something that
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i'm gonna show you throughout the yeah our what potential benefits that might be of these human local exactly
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so his have fairly simple structure of human mogul because acquired your draw this out every time you talk about this
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so we give every mormon sect right building block here a separate simple
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and then assemble them together depending on the structure and really there's only five billion girl
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look also go lactose which we know forms lactose and then in addition to that
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we have an s. to go cause i mean if you goes and so i guess
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so five building blocks and depending on how you put them together you get different all exactly
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so it's a little bit like lego bricks and you can imagine if you put lego bricks together you get the get a car
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were you get a little plain and you can imagine these two things to different things like that plane that's different
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things the car that's the same for the on exact words as well that's fairly simple structures ah but structure determines function
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and it can get fairly complex that's my daughter getting the thousand two hundred
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pieces legos said here for christmas uh doesn't get that complex so it's not that
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okay so let's take a look at all because separates and different structures all
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human mogul exact whites have lactose at the reducing and screw goes and collectors
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and then they get extended by dissect white units in different linkages um they can be branched
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for the allocated so you see already this gets fairly complex either very long what branch
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you can modify these structures with few colours in different languages if you add a few
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goes on lactose to get to focus on actors to a file and three focus select those
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or if you add few cars at the growing change it gets different only sec right so
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he an example for these for all exact words they have the same almost like what composition
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but you put those lego bricks together in different ways you get different
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structures and we think that these fall exactly it's indeed have different functions
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it's a bit more complicated from there you can also add side i
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guess it's i guess it introduces a negative charge to it's got boxer group
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as silent as a tomb lactose you get three six i liked those and if you add it to the going chain
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you get different structural isomers you can add more than just one side i guess it like down here in this structure
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um and the important part really is that there's about a hundred and fifty
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two hundred different all exact words identified so far and every man makes different ones
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it's almost like a thumb print huge variation from moment to moment gonna show you the next useless
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so what are we gonna focus on what's my that focusing on one is maternal drivers
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what contributes to that variation on exact what composition between different models
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what's the benefits for how infant health and development
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and then can we learn from human milk and take some of that
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knowledge and apply that to develop new therapeutics outside the infant space for that
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so let's take a look at the uh maternal drive us first
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look at this light this is data from the child chord in canada and spot a thousand two hundred subjects where
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we have all exact white data for and uh you see it on the bottom here every bar is a different subject
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and on the y. axis you have in different colours the concentrations of differ not exact
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it looks very different like that is low amounts in the samples very high amounts in these samples and even
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if you look at relative abundance lee said it all two hundred percent the pattern looks very different from tomorrow
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like i said this is like a thumb print on this
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you can take a look at all the sec white data slightly
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different this is the principal component analysis in the three dimensional space
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and you see here every job is an example it's about ten thousand examples in this plot
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and the closer those dots are together the more similar the all exact what composition
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of the less or the further part those dots the less similar the all exact composition
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just by looking at this and so this is collected from ten thousand samples us at approximately
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and really from almost all that most of the samples come of course some of
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the market we relocated but we have almost every continent covered and many countries include
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so you can see already this distribution him these two clusters right and left
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what is that the two different types of models buys buys the such a separation the only segment composed
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if you go through this and separated by where the samples were collected and watch which
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cool what they come from you see for example here the canadian child chord in red
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and then in comparison i wrote about as project collected in india in green and there's some
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separation mike and top down and top and bottom but that doesn't explain the left and right separation
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if you separate them by different characteristic you could actually see ah that explains that's rich what is that
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that is what we call the secret is on the non secrets
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what does that mean so that is genetically determined specific mutation in enzymes are
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in jeans that in code enzymes that ad few close to your exactly it's
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that shown here in the corner that is it ends i'm here called few postal
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transfer is too few to that as few cars specifically in this awful want to linkage
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there's another enzyme feud three future so transfers three but as few goes in
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this awful one for all for them to be linkage depending on the underlying structure
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it so happens that there is people among us that have
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a specific set specific steps so that's single nuclear type polymorphism
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that inactivate this g. so that ends i was completely dead it's a notation that introduces top coat on
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and these moms or humans in general can no longer at few goes and does all for
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one two linkage so that if you three and that explain the difference between these two different clusters
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that's one base pair one base pay the genome that changes the entire composition of human got exactly
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it's not just one on exact where that's not missing or in the
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low or high abundance the entire on exactly a profit is completely different
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one thing on the polluted polymorphism
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so the secret is here have an active you too and the non secret is happened inactive feud
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and you could map this out but different cool it's this is again
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data from the chart cool word in red you see the homozygous snaps
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orange is the head was i guess nips and white is the
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while type uh to water bills you see how that last is out
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so that's you see greater and nancy
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you can do the same thing with few three so that's the future so transfer is three and you can see this clustering as well this time you have
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the dark spots the homozygous nips down here on the bottom orange somewhere in
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the middle and white on the top so you can draw a line like that's
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eventually can cluster those in secret a positive do is positive in this problem
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here so that's active few to sorry uh interactive you two and a active you
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three you can go through the different weapons and you see how genetics really
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determine the august segment comes on a global scale this is not just one august
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so we knew about future in few three already but we can take this a
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step further now and look through different all exact words how they associated with different enzymes
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and then try to understand which and sam's really are participating in
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the synthesis of human mogul exact words which we don't know yet
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they still an entire text book page of biochemistry that needs to be read
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so here for example we have a silo transfer is um s. t. six go one
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that you don't really see contributes to any of the clustering here but you see
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that is individual exact words of the strongly associated with snaps in this specific g.
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and here specifically seasick sigh lactose which uh this and so here um
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catalyst is the reaction helps endings i guess it in two six linkage here
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and you see it's not a loss of six abductors is actually increase of
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six i liked as many have that's that so this is a gain of functions
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oh and that does not related to us how it relates to a
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similar august at where that's extended structure l. s. d. c. but not
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having steep excess critically associations between different snaps in different genes and all
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the segments and just genetics play a major role in all exact what composition
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um so now we're using gene was surging what association studies transcript
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l. makes h. m. o. makes and then use in silicon pathway modelling
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and eventually in bigger target validation to unravel the pathway of human like presents
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again it's not known how most of these all exact what a synthesised in the human memory
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and that changes depending on where you are on the planet
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for example if you look down here improve or really in south america in general most moms
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a sea creatures and half an act if you too many percent ninety five percent in other countries
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that's different on the african continent you find twenty twenty five
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thirty five to forty percent of the monster done on secrets
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they don't make the specific always so make up at all exact rights but they all exactly profit is completely different
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that really makes you wonder what your exact words due to the
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infant to the mom in different environments in different parts of the world
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all because accurate composition changes over the course of lactation i see for
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example three selectors goes up in concentration six directors goes down to use an
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anti goes up you can go through multiple differ not exact words and you
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go through multiple different words and you find the same trends in different groups
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it also seems to change uh and depending on the season so we found in the canadian court
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uh and others have found that uh in a in a coding gambia before that is specific all exact was the change
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concentration depending on where you are in the season can be very extreme dry season wet season africa but also happens in canada
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so we don't really know why that is somewhat contributes that um but this seems to be seasonal variations all
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we've also seen that all exact right total amount is different
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where the mom had already a baby or not so the more
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uh infants uh we're already here the higher the august i quit concentration
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that is not depending on age some maternal age is not associated with all because secular composition
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and will admit mode of delivery isn't it doesn't matter whether you deliver rationally you
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were by c. section for the old exactly it's it doesn't seem to make a difference
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so that's the genetics and i think there's a lot of questions that we need to answer in that part still
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but is many many more other questions when it comes to much all drivers for example what about i don't exercise
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can be manipulate altogether quite composition that what we don't know we have some data here from an uh a
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mouse model my snake all exact rights to to be precise mostly it's we sell little bit of six s. l.
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and my so much easier to work with when it comes to
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changing diet and putting men on an exercise regime so you can measure
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trees i like those concentrations in mouse smoke and then put the mouse
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on a high fat diet and you see three selectors concentration goes down
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you can exercise the mouse and the three selectors concentration goes out
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and you can do the cool experiment to put a mouse and a high fat diet and then exercise it
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that's all i felt this morning really uh and you see that those two
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effects even each other out now you're back to almost normal we were before
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of course this is mice we don't know if this happens in humans we have
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some data or a former collaboration at baylor also from a collaboration in arkansas all
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that points in the same direction silent all exact words seem to respond to five that died but
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also to exercise so we're we're working on that right now to confirm that but it seems to hold
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then we have some data that showed that using probably
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onyx during pregnancy changes the august second composition during lactation
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what about much on how station diabetes chronic inflammatory diseases
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how does that affect all exact right compositional composition in general we we don't have a lot of data
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um how about using medication how does that change all exact come which no
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data whatsoever so lots of question marks still when it comes to maternal drivers
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why is that so important why do we need to know what changes all exact what composition well if we identify
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that is specific all exact words was specific or exact word
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profiles that are potentially beneficial for the infant or form or
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then we will know how that actually works how to manipulate that can be put mama specific diet
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or on a specific supplements to enrich for specific all exact words that we identified to be a beneficial
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so any income housing developments space before we get to that we need to know what happens to be on exactly it's meant baby just
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right so all exact words go when they're resistant to the low p. h. in the store make
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and to the back where they can push what enzymes but one person gets absorbed in the small intestine
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and the rest you think it's degraded by bacteria in the cold on word cue intact excluded in the feast
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and you see this huge variation hit tend to eighty percent excluded that's saying it's either everything was nothing
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and it's completely meaningless if you think about it but really depends on the stage of
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lactation very early on you find a lot of all exact words that come out intact
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then the micro by homes somehow establishes and learns how to deal with these all exact rights
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and then you find a lot less all exactly it's coming out intact because now you're bacteria starting to metabolism
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and then the words meaning when you introduce other fruits then you find more intact oregon seconds but also other
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like ants popping out uh interface so depends a bit on where you are that's why there's such a wide range
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so what does all this egg whites to give you this one cartoon him go through this uh quickly
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uh we always talk about humour got a separate has been prepared okay right so that's the fruit for buttons
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and that might be true and that might be a lot and we start it there we call mommy by on which is a combination of
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the centre for mike upon innovation led by rob might in san diego and to our money
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course everybody try to understand how human mogul exact words and other mail components impact the mike about
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but we think that it's so much more to it you think h. m. o.'s are way more than just put a box
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we know that they and the micro bills something directly act on the bad guys and keep them in check
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we know they're entities it's gonna show your slide on that in a minute that directly modulator previous else
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and they also impacted me insist either locally in the got one a systemic like
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number one percent is absorbed sounds like it's not a lot right one percent electable
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but fifteen grams going in abilene or and this is every two to three hours the kinetics uh tell us
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that there is decent concentrations of all exact words in the ins and not a defined in maternal circulation as well
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so there's local affected the got and then this systemic effects
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and we believe we are i seen this i spurred before we think we just really now understanding what these all exact words
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to where they go what target organs they are and what mechanisms
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are behind us so that is a lot to discovered this text
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i thought about a little bit about entities it's not gonna be my first story on in from hell
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what is is actually mean entities it so we have this pathogen
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here that approaches the interest levity of cell and to be able to
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hold on in this very dynamic with the euro they need to somehow attached at the it's it's
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and you can imagine if you're bacterium you're swimming around in the intestine lots
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of movements you wanna hold on to something 'cause otherwise you out pretty quickly
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so the way they hold on is by interactions between two like tons that's like and binding proteins
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and like ants sugar molecules on the service off everything
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it's like okay thanks thick layer offered like a protein correctly
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and that is important for bacteria to be able to proliferate and in some cases the invading cause disease
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now if we go one step back and look at the same diagram here but now
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in the presence of human mogul exact words that really common constantly in very high concentrations
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and it turns out that these humid august separates resemble some
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of the uh episodes that we find on the like okay lakes
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they serve as soluble decor receptors buy into the bacteria are
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directed no longer bind together the us else they get fleshed out
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so that's why we believe that these and the mike i'm the adhesive
00:20:23
effects of august sec rights protect us from some of the infectious disease
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one example i hear that we've done with large segment that uses to use it's right next to me uh in the office
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funded by the gates foundation of a specific you look at the back attached so that enter pathogenic
00:20:43
and we found in tissue culture that in the presence of
00:20:46
your mogul because acquired e. beckett patches last year with the assaults
00:20:51
attachment is not a very good measurement for for um disease potential effects specifically causes
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these lesions format with the s. l. c. d. high that here in light green
00:21:03
we can measure those lesions that's the damage that you pack is doing on the appeal sounds
00:21:08
and in the presence of your local because across the significantly less regions on it's it's
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this is done in tissue culture when repeating this in a overnight says well human
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open minds and also we've shown that this works in unit on mikes so you can
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add all the segments of the diet and you recognise action drop significant
00:21:30
so that's one example and you see here diarrhoea is
00:21:33
a major problem two thousand two hundred that almost per day
00:21:37
ah i see every single day children under the age of five the back
00:21:41
is not the most uh common pathogen for that uh rather buyers is one
00:21:47
of the major cost that so we look to draw the virus infections well
00:21:51
we work with such a right money here at baylor in their marius test group
00:21:55
and specifically at a rubber is called g. ten p. eleven which is
00:21:59
despite protein that sits on this specific role of errors that is found
00:22:03
in areas in india specifically in the in ages four to five weeks of like
00:22:08
and we thought well entities of must work it to likens i'm often
00:22:12
the binding let's test it out and show it get published and out
00:22:17
so uh so actually grew a everything yourselves at the buyers looked at interactivity and to our
00:22:22
surprise we found that the specific all exact whites
00:22:25
it increase the interactivity of this specific whatever strike
00:22:30
and we thought oh this can't be right as as a must be wrong because you know human
00:22:34
look is supposed to protect us so how can this be right we must be them doing something wrong
00:22:38
so we repeated this a few times difference else different conditions are be found the same results
00:22:47
we want to confirm this and went to india uh and it looked
00:22:50
specifically at the moms in the in in the infants they're collected no examples
00:22:55
analysts them for all exact rides and looked who
00:22:58
which invent developed or or was infected with a virus
00:23:02
and who had symptomatic and a symptomatic infections it is the difference in the on exact words
00:23:09
and we found it is a difference in the old exactly it's this is looking at it more on a global scale
00:23:13
here this is a principal component analysis and you see already
00:23:16
in red is the inference that are infected and show symptoms
00:23:21
the milk all exact what composition in with a good corresponding moms and the cluster slightly different
00:23:29
and then if you look at individual exact rights we find the same
00:23:32
i guess accuracy we found to increase interactivity in the in the dresses
00:23:37
where high and the milk of moms with the infant got infected and had sometimes
00:23:42
so the basically overlap between the individual data and what we found in the mother in vancouver word here in indy
00:23:52
so that was a surprise to say the least is it possible that there are pathogens now that
00:23:57
i getting ahead in the arms race are and are trying to take advantage of your remote components
00:24:04
if that's the case we need and all that
00:24:07
and can we use that knowledge then to get ahead to develop better vaccination strategies
00:24:14
the trends out drawback which is the buyers that is uh the the
00:24:17
backs of vaccine that is used in that area is alive attenuated to strain
00:24:23
and we can increase the infected the overall uh back as well with the same
00:24:26
august separates that showed an increase in effectively in the regular strain that be fine
00:24:31
so can we had all exact rights to vaccination strategies and make vaccinations more efficient
00:24:45
so to summarise this part specification malls are associated with increased rather virus infection
00:24:51
and again this is a specific role by striking this is not fall of viruses
00:24:56
and this is an opportunity to improve oxidation success
00:25:04
another example is on well
00:25:08
our our exact words related to infant but we had so much on that with the micrograms group if you see
00:25:13
the specific all exact words that somehow associate in cool words within from growth
00:25:19
a fat mass and all those uh parameters and to here we work
00:25:23
with can my cousins group in copenhagen yes is very unique cool word
00:25:27
off exclusively breastfed infants with excessive weight k. so if you look at the
00:25:33
um the or characteristics of these uh that is the highway great high waking group
00:25:39
and there is the weight for age these were were two standard deviations these are getting made extremely quickly
00:25:46
and then the normal way group here is that between minus one and plus months that age
00:25:51
and we wanted to know is the difference in the only segment composition between these two different groups
00:25:56
i can only guess egg whites explain this immense excessive weight gain in these infants
00:26:05
so we look at total exact writes it was no
00:26:09
significant difference in total exact words between the two different groups
00:26:13
we looked at h. m. o. one few calls as a total measurements of
00:26:17
you cause relation there was a significant difference more few goes in the highway to
00:26:24
we also looked at h. m. o. bonsai elation and that was not
00:26:27
significant difference so that was the trend in the worst dilation the highway group
00:26:32
and then we looked at specific individual exact words and we found that
00:26:35
specifically to f. l. to focus selectors was significantly higher in the highway
00:26:43
me and he was significantly lower in the highway
00:26:48
so we have different hanukkah separates that seemed to be at least associated in different ways in this case with highway
00:26:55
well this is a exploratory study it was only thirty
00:26:57
mother infant is very small word although we got significant results
00:27:02
and we want to confront this well let's go uh i mean we put this
00:27:05
refers that so this is now on a linear scale to a felony an anti
00:27:09
just to give an idea where we are currently with adding these
00:27:11
all exact words to infant formula is your one milligram per mile
00:27:16
threshold so we're way below that way below the range is that we measure in the study here an eternity is right in the middle
00:27:25
and so in case you were wondering how we know adding two of our our kids are gonna get
00:27:28
fat now uh we're way out of that right and so at this point no reason to be concerned
00:27:37
so that was thirty mother engine pierce where we work then with alex from and the and the doctor out of of spoke
00:27:43
yesterday now went to uh finish school what the steps cool word
00:27:47
is a fairly healthy uh infants now a five six years old
00:27:51
and we had a chance to look at eight hundred examples from pretended not then it's
00:27:56
and we found the same thing
00:27:59
this is a little bit presented a bit differently here this is
00:28:02
the first five years of life is your height standard the deviations and
00:28:07
you see that the highest what how into of our concentration if you
00:28:11
a higher height and the lowest what are gives you a lower right
00:28:18
so saying that we found earlier them what to a value half in this case the high you are but this is the same for weight as well
00:28:25
and the the less to a value have this more
00:28:33
it looks the other way around foot near the d. just like we've seen in the in
00:28:37
the in the school board and if you take the ratio of two of our annual anti
00:28:44
you see that this holds up nicely and holds up until five years of age this is significant until five years of age
00:28:50
so you can imagine depending on what all this egg whites even what the ratio between different all exact words are you get
00:28:56
the toll scandinavian or you get the smaller german guy that
00:29:00
would be me and to as a different of how standard deviation
00:29:05
just by looking at the two of 'em yell into issue i think this is quite remarkable
00:29:14
so can specific h. m. o. s. i. associated with income growth uh infant and child would go
00:29:20
we need to study goes out these this is just an association of is there really a 'cause out to be like this
00:29:26
how does this work
00:29:28
and this could be a great opportunity to improve growth when it's needed
00:29:37
another example is in the premature space just one slide although this is work that
00:29:41
now has covered the ten twelve years of the work that we're doing it now
00:29:45
um but we try to summarise this in one one slide here briefly what is neck and why is it
00:29:51
important five percent of all very low birth weight preterm infants develop this often deadly it does not this or
00:29:59
we know that preterm infants receive human milk right six to ten fold lower risk to develop that
00:30:06
is the connection with the channels and a journals explain this difference
00:30:11
so we set out about ten twelve years ago to test this hypothesis
00:30:16
that your remote already separates us somehow related to the lower incidence of neck
00:30:21
um what we did is we isolate august backwards from pullman don't
00:30:24
amount to get the entire collection of your remote all exact words
00:30:29
has that in in people model in this case in in in the right model
00:30:34
we found that it isn't the fact and we want to know which structure is it so we
00:30:38
went and used multidimensional chromatography to really narrow down which structure is responsible for the fact that we see
00:30:45
and we found that this is the only sec ride that was responsible
00:30:48
for the protective effect of the isn't t. i. silo liked and controls
00:30:55
and we presented this work and we got slashed if your time say well this animal model is not really
00:31:00
good when it comes to nectar doesn't or collide is you know this has nothing to do with that we
00:31:09
uh we looked at the chemical space around because seventies with a few studies the worker cameras to make
00:31:15
derivative somebody found that these and he was the most important component to to uh to be effective here
00:31:21
but we wanted to get around that criticism that this is just an animal so what we did is we
00:31:26
designed a mother infant peer cool word probably recruited specifically
00:31:30
mothers and they're very low birth weight instance in north america
00:31:35
collected no examples every second day in the mail that went into that instant on that date
00:31:42
analysts they don't look all exact what composition and compared all exact
00:31:47
what composition between inference that develop neck and instance that did not develop
00:31:55
and we found to our surprise that the same on exactly that was protective in the animal model
00:32:01
was lower in the mail that was given to those inference that later developed neck
00:32:06
so it was protective anyhow model if it wasn't low concentrations in mom's milk
00:32:12
that infant would develop neck was a clear match if repeat this and this and
00:32:16
this study in south africa the meantime and found the same on exact what being associated
00:32:20
here we can say well it's an association it's not cause audi but since we have the animal data as well
00:32:26
it's a nice overlap that now gives us more confidence that we can move forward a technologist
00:32:33
it also gives us some confidence that the model is not that bad after also
00:32:36
studying the mechanism ah with the compound will give us some insights how this works
00:32:42
this is an example in the payment
00:32:46
on specific call
00:32:50
oh do time
00:32:53
so it's okay good a good ten minutes maybe to talk about something
00:32:57
completely different another seminar is about an innate impact on many a night
00:33:03
but we have very exciting data to show that what we learn from
00:33:06
human mogul exact words in the infant space in the new nail space
00:33:10
can be very valuable maybe maybe it uh go with and develop new therapeutics what
00:33:14
else at the other end of the last thing so when we talk about frailty
00:33:18
others roses that's why this those kinds of things we think that what exactly as
00:33:22
can be very powerful and that's accessible and i'll show you some good on that
00:33:28
so this is what chronic inflammation it all started on two thousand fourteen or non hike with
00:33:33
a friend and it's fun to still chords is also prefers it uses the this guy over here
00:33:39
and uh the hike is a up to potato chip recall that in san diego
00:33:44
okay and this is the chip is sitting on here my daughter takes a very which will be
00:33:50
and uh so it's a philips working on on macrophages on it
00:33:55
mattered information is that by saying that we've need to find a
00:33:57
way to work together i would love to test your exact right strode on my macrophages and see where it's so we did that
00:34:05
again i sat august backwards from human milk and through that on his macrophages and we found wow
00:34:13
sniff a significant reduction in i. l. six and i won't be that when
00:34:17
you stimulate this l. l. p. s. and then throw your exact words on
00:34:22
'kay
00:34:24
we then use the same approach to identify specific autistic words that are responsible for that is that
00:34:30
yeah we found that three itself we select those is the obvious effort that lives most of these facts
00:34:38
we found that this works in a mouse cell line
00:34:42
it works in primary sounds
00:34:45
it works in human cell line as well and works in human patients as well
00:34:50
and we've shown that this is not just working on the on a level that
00:34:53
works in the protein possible so the secretion of the satin hands is significantly reduced
00:35:01
we then went in and did those finding nice it fifty studies we found i see
00:35:05
fifties on twenty michael graham paramount which is close to what we have in the infant but
00:35:11
it's not unreasonable concentration
00:35:15
and we want to know what is the mechanism houses work
00:35:18
outs three years or read using these very prominent confirmatory said okay
00:35:24
and to make this show uh the story short i'm going to the next lights quite quickly
00:35:27
i'm gonna show you want a summary in the end so we want to know what's the receptor
00:35:31
is it somehow interacting directly with the t. love forest if we're up yes and we found the that's not the case
00:35:38
so but it on a sequencing we found that we stimulate the cells with l. p. s. to get a bunch of jeans up and down regulated
00:35:45
but it's not the same gene city effect with resounding add that to the next
00:35:49
so it's only a few genes that are differentially expressed in the presence of three it's
00:35:54
so brian like that there's a direct interaction on the receptor otherwise you could shut down the entire proper
00:35:59
then it's a silent like and so we thought well maybe it's just eclipse and we
00:36:03
have the cigarette experts white one floor down at you by key and the and the
00:36:09
uh actually say so they had knockout mice already running around we just need the bone
00:36:14
get the ice to get the macrophages isolated and see if our compound still has an effect
00:36:20
and it turns out it still works
00:36:23
knocking out those sick lex is not having an effect cigarettes are not the receptors
00:36:33
so what is that it's not really becomes a fishing expedition or
00:36:37
it could be anything is very difficult to narrow down black imploding interactions
00:36:41
if it is not very high so that you pulled on experiments mass back very difficult to do that with like
00:36:47
so we went back to our ah our ne sequencing data here
00:36:53
and we look which genes i actually don't regulate what three years now and
00:36:57
not a surprise it's the genes that are associated inflammatory response cider kind second activation
00:37:04
uh which teams up regulating the found oh that's interesting the is bunch of that that metabolism involved
00:37:12
and we found that that is all these genes of
00:37:15
uh associate with what we called accelerated the love for resolution
00:37:20
when you switch on the macrophages me to switch it off that's the
00:37:23
resolution face faster you can switch on microfiche off that that's information yeah
00:37:30
so turned out
00:37:33
there was a paper published uh just the year before we looked into this from a guy it uses decreased last lap
00:37:39
that showed that killer for signal and speeches on your inflammatory response here very early on
00:37:44
that one to six hours that's been on the side uh kinds of realise that's active microfiche
00:37:49
but then it gets switched off but this pathway down here that includes a lot
00:37:52
of people it happens and that happens in the twelve to twenty four hour h.
00:37:57
it turns out that almost ninety percent of the genes that we've
00:38:00
sought induced by three is i'll have something to do with his padding
00:38:07
so we went to chris asking can you help us with this can be through
00:38:10
or compound on it and then do chip seek so we did this experiment here
00:38:15
just to cut this very short now because it's very detailed but just to show with a really going deep into this
00:38:20
so if you look at two hours just l. p. s. you see all these uh enough to be all these
00:38:26
different inflammatory pathways go up but he you see the the bit metabolism coming up and at three us out books
00:38:37
skip this one here and go right to the model i make this a bit faster
00:38:44
so what we think is gonna happen is happening um skip this now what we think what's happening
00:38:54
as much as well i
00:38:59
i haven't seen too many slights
00:39:06
okay so here's the mall what happens when you add up yes or another uh that's uh stimulator switch
00:39:13
on the informant response you get to this point
00:39:15
right information switch on decision early phase of macrophages activation
00:39:21
well we still don't know what the receptor is resell somehow interviews with this program here
00:39:27
shifts the marker for each phone activation to resolution much faster
00:39:31
what happens in twenty four hours now happens and six hours
00:39:35
the microfiche get switched off much faster than that but profile
00:39:38
changes rapidly much earlier these these uh these puppets pop up
00:39:43
uh we see the receptor for it to be can knock out
00:39:48
now gives us that speech off so the macrophages switched off march first
00:39:54
now why is that important
00:39:58
one of the diseases where chronic inflammation macrophages information plays a significant role is remote part of flights
00:40:07
one percent of the world population has already
00:40:12
that's about one point three million people in the rest alone and women are
00:40:17
factor three times more than men they may also hold the secret on potential therapeutic
00:40:26
so we collaborate here with my popcorn nazi putting it uses d. and
00:40:30
tested out our three years out in a are among the most small
00:40:35
put three select was in the drinking water first to show you
00:40:38
we we measure the paul thickness here uh throughout the time of
00:40:43
of a disease be induced to disease by giving it a college an antibody pause swell up
00:40:50
given happiest bruised and the pause really get really and fly
00:40:56
no yeah at three us on the drinking water and you see there's a significant difference in the possible
00:41:02
a lot less possible i mean if you show this to someone who is in the array
00:41:05
field will tell you oh this is what we see without enough of anybody's this is very comparable
00:41:13
and not only that at the end of the study see they it's less
00:41:17
information less bone roche and less cartilage damage all those read outs that a
00:41:22
typical for arthritis are significantly reduced in the presence of three us up in
00:41:27
the drinking this is not an injection this is just giving something in the drinking
00:41:34
so we tried this on the second models genetic model and just to make
00:41:37
the short we find the same in a three is uh reducing departments significantly
00:41:43
in the meantime there's a group in south korea that use the third independent model
00:41:48
also tried three s. l. and also found that three s. l. significantly reduces what what's
00:41:57
and that's of buttons in concentration
00:42:04
so here now we have data from in vitro model some model we have data
00:42:09
from in beaver model actually to be independent models that we show that this compound works
00:42:14
is there a human court where we can see if there's really translates to human a disease
00:42:20
now that's difficult to do because most of inference don't develop arthritis of course but
00:42:24
we shot this data to christina chambers that use easy she said well that's interesting
00:42:29
because we have so many women with our re that don't remission at the end
00:42:33
of the first trimester and then they flare up again towards the end of press the
00:42:40
well that's interesting because it turns out that he memo got exactly what specifically three
00:42:44
s. l. pops up in maternal circulation at the end of the first trimester during pregnancy
00:42:52
is there anything yeah is there is a link between these two things
00:42:57
so what do you do if you wanted to record study here go to canada you go and call megan as often as did you ask your
00:43:02
mom's if they had arthritis and it turns out that they collected data
00:43:06
on a white is ah they asked months have you ever had our it
00:43:12
and if they said no we never had that we call that zero that's all control group
00:43:16
have you ever had already but you're currently don't have alright so that's a remission group that's our group one
00:43:23
and then do you currently have alright still have alright while you're actually giving as an example that's our active
00:43:30
and then we looked at the august like what composition actually found indeed no difference in
00:43:35
total exact words but significantly more three d. s. l. in the moms that went in remission
00:43:41
so a very nice correlation now between the in vitro data in tissue culture
00:43:46
most models and coming in with the cool would like this where you
00:43:49
show that monster go in remission making with three s. l. and produce seven
00:44:01
so the selectors maybe both a purely treating prevent up right
00:44:07
but there's other diseases that are related to comic information chronic macrophages formation and
00:44:12
wonders cardiovascular disease the number one killer in the world when it comes to
00:44:17
uh and you know that you're eighteen million people die from columbus that is that's a heart attack or stroke every single here
00:44:25
and macrophages place usual that that's your form so that's why that's the
00:44:29
phones also some couple yellow yellow yellow bits and then clog up your arteries
00:44:35
to make this story short again working with philip here we put minus uh that
00:44:39
had a l. a. l. r. knockout that's your receptor knockout put on high fat diet
00:44:46
with them without we'll sell and then we looked at other scrolls assessment
00:44:51
no difference in food intake no difference in weight gain but
00:44:57
a significant difference when it comes to matters quilted x. uh in the examples on three or so
00:45:06
and you can measure that in three d. you can measure pluck size and the crowd of course and all these things and
00:45:10
again this is significant difference in all those measures in the
00:45:13
minds aren't we sell it's can be take a human not component
00:45:18
and apply that to patients that would potentially died from heart attack or stroke
00:45:23
and natural component that we give to babies every two three hours anyway potentially say
00:45:28
this could be a real game change
00:45:34
so somewhere here three select those maybe a potent therapeutic to treat him prevent cardiovascular disease
00:45:41
that's just to diseases really ah are a collie was the disease
00:45:47
a talk to the button area so many other things accessible box
00:45:52
b. c. d. diabetes i. b. d. breast cancer there's always a link somehow to human organ
00:45:57
to breastfeeding and we wanna identify how this all works and we call that element one shot
00:46:04
we wanna know what is in him how this works and how it could protect people talk before the infant
00:46:09
formal but also for adults that at the very very other and often aspect
00:46:17
i keep you with that and
00:46:18
take questions ah
00:46:24
sticky first um how
00:46:28
i know any food which can be as you mentioned uh uh
00:46:32
inhabitants of adherence of micro organism to resort to select the sound
00:46:38
surprisingly i like family from i think one of the important carbohydrate mao
00:46:43
hi my now that i'm i'm willing to offer that you don't have any mouse
00:46:50
uh_huh although i'm i'm home i know for a fact can ha ha ha ha
00:46:57
because again that makes great difference with respect to accomplish much influence of yes
00:47:04
so no man oh same humour going separates mendoza specific to yeah
00:47:08
and like lance uh don't find it in human quality support at all
00:47:13
which might give away a little bit all the synthesised in the memory land for you find biblical proclaimed you
00:47:17
find like a pro deals yeah yeah one for sure in the no yeah but you don't find it remote august
00:47:23
yeah and the other person was about the also to three other
00:47:26
two six uh links so i guess it's we find both well yeah
00:47:31
and uh in different interesting here is you have and also to sixteen silent as it not only on the
00:47:36
tomatoes but also internally hunk of man and that is very unique to uh to human not only 'cause i have
00:47:44
uh_huh okay live search for first amendment over
00:47:51
how was huh ah congratulations it really was a fantastic presentation excellent work
00:47:58
i show that the data that you present day all the you hire ah ha
00:48:03
ha uh of children with twelve how that data is corrected for me aren't all height
00:48:09
is going to force of yeah that again yeah the results how
00:48:12
high he corrected it can't just be for the need parental height
00:48:18
for mom slightly me well yeah because i mean it could be that the same way that genetics
00:48:23
plays a role in determining a higher to repel might determine that the parents are high at taller
00:48:29
unless the channel is taught not because of it without that because of
00:48:32
the current uh hi good point yeah some leniency in in this little
00:48:40
ah
00:48:45
hi
00:48:49
yeah because they're not they're chow line and part relates to matter no height
00:48:55
but at four years of age relate to me during the height
00:49:00
the fire sometimes also plays a role news reporting thing looked over
00:49:10
do you really beautiful
00:49:13
and you build them which i think you will which uh i wanna
00:49:18
focus on the the story don't do what else would you rule rose
00:49:24
a lot a lot is at least in the
00:49:27
man effect specific receptor sounded only different huge interest rates
00:49:33
do you know the the only person writes blinded receptor on ventral sites in any
00:49:39
specific manner hum yeah we we don't know exactly what the mechanism is behind it
00:49:44
uh it turns out so so the original hypothesis man went in was to look for why is
00:49:49
it that this specific role of a strain as
00:49:52
as a as a a specific affinity cheese onion
00:49:57
why is it that only in the first four to six weeks of live this specific
00:50:01
role of a strange found it doesn't in fact instance which even later it later h.
00:50:06
so is there anything in the intestine ah that like an swatches in interest and the
00:50:11
difference between an innate and later on in life so the receptor wouldn't find it funny
00:50:16
only a little over this is really typically in any younger children
00:50:22
but nothing really really young and then you won't be you don't you
00:50:25
want to use rules just specific policy the g. ten eleven is specific
00:50:29
for the first four to six weeks and you don't it specific yea
00:50:33
but you don't know what they're going to listen to each of mm no
00:50:38
okay the second question is if it does alter the interaction with the lowest and a bit him in some way
00:50:44
do you see any changes in the induction your disciplines we haven't looked on expression of disease
00:50:52
we only looked insecurity in the in the channel and then in the in the
00:50:55
cool we looked at it with a is in fact injection and with the symptoms yeah
00:51:00
the last question i had was really do not know why does but but he like close to you uh_huh
00:51:06
so the good example blasted in with the infection should just a lot of decision models
00:51:11
a little people but not in children in the neural settings they had a lot of
00:51:16
culmination but you don't hear much much clinical disease how you
00:51:21
look at any other box besides what you talked it would indeed
00:51:26
unit would be yeah we we voted with a bunch of lots uh we looked in addition to effect we
00:51:30
looked at capital but uh we looked at different people i. e. a. c. e. u.s we looked at the checks
00:51:35
uh we looked at the end of may basilica also
00:51:40
claudia but you look like you really so we should be something really just to disabilities another very unique
00:51:46
setting in which is maybe you you know you may have found a coke bottles still it's for example
00:51:52
you can treat lewd arthritis to one all infractions under israel's uh_huh
00:51:57
be reading reviews to alan studies thank you like to go to high mission done on the third row over there
00:52:06
uh_huh
00:52:12
across
00:52:14
so my question is um do we have any
00:52:17
structural billions on um the higher um most collections
00:52:24
oh but the express of blue um type two structures it it'll
00:52:29
subfolder controls which on to expose constructions yes uh so the yeah the high
00:52:34
molecular structures uh go down in concentration quite quickly or uh we see that
00:52:40
they may be top fifteen or top twenty only separates our at least for
00:52:43
total concentration the predominant players and the moment you get larger the construction troughs
00:52:49
um i'm not sure exactly what lot types uh you
00:52:54
find on the different uh higher molecular the the segments
00:52:58
uh depends certainly also on the secret on the noise respect
00:53:01
upset as well i mean that really drives that's tremendously um
00:53:05
but i would imagine that to that that uh we kept on the larger structures as well what i was
00:53:10
wondering because we followed the local h. one and lose
00:53:15
the peace functions so no l. x. m. is office yes
00:53:22
okay last question from the third row there uh_huh
00:53:26
thank you for your nice dilution of the legal teams
00:53:31
could should help and a beam years will isn't that huge abbreviations for the
00:53:36
can you use it's my question didn't find any difference in the
00:53:41
menu page mother and when you do mother in the it's the kinds of the only goes to collapse
00:53:47
yeah i think it would be that five differences huh when the
00:53:52
menu digit model well as well as to when usually find a difference
00:53:56
yeah so we we haven't looked at that but there is data that came out of u. c. davis uh together which of course group as well where
00:54:02
the specifically looked at mom's uh i believe it wasn't on the dash but
00:54:07
i think they also looked uh with and do crunches in the damp yeah
00:54:10
and there were differences in august but it's a good second position in most of the ah on it yeah
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