Rob Knight: How our microbes make us who we are

410,490 views ・ 2015-02-23

TED


Please double-click on the English subtitles below to play the video.

00:13
We humans have always been very concerned about the health of our bodies,
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but we haven't always been that good at figuring out what's important.
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Take the ancient Egyptians, for example:
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very concerned about the body parts they thought they'd need in the afterlife,
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but they left some parts out.
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This part, for example.
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Although they very carefully preserved the stomach, the lungs,
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the liver, and so forth,
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they just mushed up the brain, drained it out through the nose,
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and threw it away,
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which makes sense, really,
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because what does a brain do for us anyway?
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But imagine if there were a kind of neglected organ in our bodies
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that weighed just as much as the brain
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and in some ways was just as important to who we are,
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but we knew so little about and treated with such disregard.
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And imagine if, through new scientific advances,
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we were just beginning to understand
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its importance to how we think of ourselves.
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Wouldn't you want to know more about it?
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Well, it turns out that we do have something just like that:
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our gut,
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or rather, its microbes.
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But it's not just the microbes in our gut that are important.
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Microbes all over our body
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turn out to be really critical to a whole range of differences
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that make different people who we are.
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So for example, have you ever noticed
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how some people get bitten by mosquitos way more often than others?
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It turns out that everyone's anecdotal experience out camping is actually true.
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For example, I seldom get bitten by mosquitos,
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but my partner Amanda attracts them in droves,
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and the reason why is that we have different microbes on our skin
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that produce different chemicals that the mosquitos detect.
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Now, microbes are also really important in the field of medicine.
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So, for example, what microbes you have in your gut
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determine whether particular painkillers are toxic to your liver.
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They also determine whether or not other drugs will work for your heart condition.
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And, if you're a fruit fly, at least,
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your microbes determine who you want to have sex with.
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We haven't demonstrated this in humans yet
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but maybe it's just a matter of time before we find out. (Laughter)
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So microbes are performing a huge range of functions.
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They help us digest our food.
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They help educate our immune system.
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They help us resist disease,
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and they may even be affecting our behavior.
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So what would a map of all these microbial communities look like?
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Well, it wouldn't look exactly like this,
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but it's a helpful guide for understanding biodiversity.
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Different parts of the world have different landscapes of organisms
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that are immediately characteristic of one place or another
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or another.
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With microbiology, it's kind of the same, although I've got to be honest with you:
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All the microbes essentially look the same under a microscope.
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So instead of trying to identify them visually,
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what we do is we look at their DNA sequences,
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and in a project called the Human Microbiome Project,
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NIH funded this $173 million project
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where hundreds of researchers came together
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to map out all the A's, T's, G's, and C's,
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and all of these microbes in the human body.
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So when we take them together, they look like this.
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It's a bit more difficult to tell who lives where now, isn't it?
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What my lab does is develop computational techniques that allow us
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to take all these terabytes of sequence data
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and turn them into something that's a bit more useful as a map,
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and so when we do that with the human microbiome data
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from 250 healthy volunteers,
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it looks like this.
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Each point here represents all the complex microbes
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in an entire microbial community.
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See, I told you they basically all look the same.
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So what we're looking at is each point represents one microbial community
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from one body site of one healthy volunteer.
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And so you can see that there's different parts of the map in different colors,
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almost like separate continents.
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And what it turns out to be
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is that those, as the different regions of the body,
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have very different microbes in them.
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So what we have is we have the oral community up there in green.
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Over on the other side, we have the skin community in blue,
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the vaginal community in purple,
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and then right down at the bottom, we have the fecal community in brown.
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And we've just over the last few years
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found out that the microbes in different parts of the body
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are amazingly different from one another.
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So if I look at just one person's microbes
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in the mouth and in the gut,
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it turns out that the difference between those two microbial communities
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is enormous.
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It's bigger than the difference between the microbes in this reef
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and the microbes in this prairie.
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So this is incredible when you think about it.
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What it means is that a few feet of difference in the human body
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makes more of a difference to your microbial ecology
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than hundreds of miles on Earth.
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And this is not to say that two people look basically the same
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in the same body habitat, either.
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So you probably heard
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that we're pretty much all the same in terms of our human DNA.
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You're 99.99 percent identical in terms of your human DNA
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to the person sitting next to you.
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But that's not true of your gut microbes:
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you might only share 10 percent similarity
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with the person sitting next to you in terms of your gut microbes.
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So that's as different as the bacteria on this prairie
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and the bacteria in this forest.
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So these different microbes
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have all these different kinds of functions that I told you about,
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everything from digesting food
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to involvement in different kinds of diseases,
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metabolizing drugs, and so forth.
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So how do they do all this stuff?
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Well, in part it's because
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although there's just three pounds of those microbes in our gut,
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they really outnumber us.
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And so how much do they outnumber us?
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Well, it depends on what you think of as our bodies.
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Is it our cells?
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Well, each of us consists of about 10 trillion human cells,
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but we harbor as many as 100 trillion microbial cells.
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So they outnumber us 10 to one.
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Now, you might think, well, we're human because of our DNA,
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but it turns out that each of us has about 20,000 human genes,
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depending on what you count exactly,
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but as many as two million to 20 million microbial genes.
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So whichever way we look at it, we're vastly outnumbered
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by our microbial symbionts.
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And it turns out that in addition to traces of our human DNA,
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we also leave traces of our microbial DNA
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on everything we touch.
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We showed in a study a few years ago
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that you can actually match the palm of someone's hand up
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to the computer mouse that they use routinely
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with up to 95 percent accuracy.
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So this came out in a scientific journal a few years ago,
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but more importantly, it was featured on "CSI: Miami,"
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so you really know it's true.
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(Laughter)
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So where do our microbes come from in the first place?
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Well if, as I do, you have dogs or kids,
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you probably have some dark suspicions about that,
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all of which are true, by the way.
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So just like we can match you to your computer equipment
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by the microbes you share,
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we can also match you up to your dog.
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But it turns out that in adults,
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microbial communities are relatively stable,
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so even if you live together with someone,
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you'll maintain your separate microbial identity
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over a period of weeks, months, even years.
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It turns out that our first microbial communities
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depend a lot on how we're born.
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So babies that come out the regular way,
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all of their microbes are basically like the vaginal community,
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whereas babies that are delivered by C-section,
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all of their microbes instead look like skin.
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And this might be associated with some of the differences
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in health associated with Cesarean birth,
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such as more asthma, more allergies, even more obesity,
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all of which have been linked to microbes now,
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and when you think about it, until recently, every surviving mammal
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had been delivered by the birth canal,
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and so the lack of those protective microbes
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that we've co-evolved with might be really important
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for a lot of these different conditions that we now know involve the microbiome.
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When my own daughter was born a couple of years ago
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by emergency C-section,
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we took matters into our own hands
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and made sure she was coated with those vaginal microbes
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that she would have gotten naturally.
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Now, it's really difficult to tell whether this has had an effect
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on her health specifically, right?
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With a sample size of just one child, no matter how much we love her,
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you don't really have enough of a sample size
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to figure out what happens on average,
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but at two years old, she hasn't had an ear infection yet,
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so we're keeping our fingers crossed on that one.
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And what's more, we're starting to do clinical trials with more children
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to figure out whether this has a protective effect generally.
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So how we're born has a tremendous effect on what microbes we have initially,
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but where do we go after that?
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What I'm showing you again here is this map
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of the Human Microbiome Project Data,
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so each point represents a sample from one body site
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from one of 250 healthy adults.
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And you've seen children develop physically.
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You've seen them develop mentally.
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Now, for the first time, you're going to see
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one of my colleague's children develop microbially.
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So what we are going to look at
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is we're going to look at this one baby's stool,
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the fecal community, which represents the gut,
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sampled every week for almost two and a half years.
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And so we're starting on day one.
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What's going to happen is that the infant is going to start off as this yellow dot,
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and you can see that he's starting off basically in the vaginal community,
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as we would expect from his delivery mode.
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And what's going to happen over these two and a half years
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is that he's going to travel all the way down
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to resemble the adult fecal community from healthy volunteers down at the bottom.
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So I'm just going to start this going and we'll see how that happens.
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What you can see, and remember each step in this is just one week,
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what you can see is that week to week,
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the change in the microbial community of the feces of this one child,
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the differences week to week are much greater
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than the differences between individual healthy adults
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in the Human Microbiome Project cohort,
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which are those brown dots down at the bottom.
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And you can see he's starting to approach the adult fecal community.
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This is up to about two years.
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But something amazing is about to happen here.
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So he's getting antibiotics for an ear infection.
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What you can see is this huge change in the community,
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followed by a relatively rapid recovery.
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I'll just rewind that for you.
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And what we can see is that just over these few weeks,
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we have a much more radical change,
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a setback of many months of normal development,
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followed by a relatively rapid recovery,
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and by the time he reaches day 838,
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which is the end of this video,
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you can see that he has essentially reached the healthy adult stool community,
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despite that antibiotic intervention.
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So this is really interesting because it raises fundamental questions
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about what happens when we intervene at different ages in a child's life.
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So does what we do early on, where the microbiome is changing so rapidly,
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actually matter,
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or is it like throwing a stone into a stormy sea,
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where the ripples will just be lost?
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Well, fascinatingly, it turns out that if you give children antibiotics
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in the first six months of life,
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they're more likely to become obese later on
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than if they don't get antibiotics then or only get them later,
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and so what we do early on may have profound impacts
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on the gut microbial community and on later health
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that we're only beginning to understand.
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So this is fascinating, because one day, in addition to the effects
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that antibiotics have on antibiotic-resistant bacteria,
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which are very important,
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they may also be degrading our gut microbial ecosystems,
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and so one day we may come to regard antibiotics with the same horror
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that we currently reserve for those metal tools
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that the Egyptians used to use to mush up the brains
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before they drained them out for embalming.
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So I mentioned that microbes have all these important functions,
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and they've also now, just over the past few years,
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been connected to a whole range of different diseases,
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including inflammatory bowel disease,
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heart disease, colon cancer,
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and even obesity.
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Obesity has a really large effect, as it turns out,
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and today, we can tell whether you're lean or obese
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with 90 percent accuracy
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by looking at the microbes in your gut.
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Now, although that might sound impressive,
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in some ways it's a little bit problematic as a medical test,
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because you can probably tell which of these people is obese
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without knowing anything about their gut microbes,
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but it turns out that even if we sequence their complete genomes
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and had all their human DNA,
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we could only predict which one was obese with about 60 percent accuracy.
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So that's amazing, right?
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What it means that the three pounds of microbes that you carry around with you
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may be more important for some health conditions
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than every single gene in your genome.
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And then in mice, we can do a lot more.
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So in mice, microbes have been linked to all kinds of additional conditions,
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including things like multiple sclerosis,
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depression, autism, and again, obesity.
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But how can we tell whether these microbial differences
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that correlate with disease are cause or effect?
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Well, one thing we can do is we can raise some mice
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without any microbes of their own in a germ-free bubble.
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Then we can add in some microbes that we think are important,
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and see what happens.
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When we take the microbes from an obese mouse
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and transplant them into a genetically normal mouse
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that's been raised in a bubble with no microbes of its own,
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it becomes fatter than if it got them from a regular mouse.
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Why this happens is absolutely amazing, though.
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Sometimes what's going on is that the microbes
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are helping them digest food more efficiently from the same diet,
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so they're taking more energy from their food,
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but other times, the microbes are actually affecting their behavior.
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What they're doing is they're eating more than the normal mouse,
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so they only get fat if we let them eat as much as they want.
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So this is really remarkable, right?
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The implication is that microbes can affect mammalian behavior.
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So you might be wondering whether we can also do this sort of thing across species,
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and it turns out that if you take microbes from an obese person
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and transplant them into mice you've raised germ-free,
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those mice will also become fatter
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than if they received the microbes from a lean person,
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but we can design a microbial community that we inoculate them with
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that prevents them from gaining this weight.
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We can also do this for malnutrition.
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So in a project funded by the Gates Foundation,
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what we're looking at is children in Malawi
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who have kwashiorkor, a profound form of malnutrition,
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and mice that get the kwashiorkor community transplanted into them
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lose 30 percent of their body mass
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in just three weeks,
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but we can restore their health by using the same peanut butter-based supplement
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that is used for the children in the clinic,
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and the mice that receive the community
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from the healthy identical twins of the kwashiorkor children do fine.
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This is truly amazing because it suggests that we can pilot therapies
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by trying them out in a whole bunch of different mice
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with individual people's gut communities
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and perhaps tailor those therapies all the way down to the individual level.
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So I think it's really important that everyone has a chance
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to participate in this discovery.
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So, a couple of years ago,
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we started this project called American Gut,
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which allows you to claim a place for yourself on this microbial map.
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This is now the largest crowd-funded science project that we know of --
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over 8,000 people have signed up at this point.
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What happens is, they send in their samples,
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we sequence the DNA of their microbes and then release the results back to them.
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We also release them, de-identified, to scientists, to educators,
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to interested members of the general public, and so forth,
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so anyone can have access to the data.
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On the other hand,
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when we do tours of our lab at the BioFrontiers Institute,
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and we explain that we use robots and lasers to look at poop,
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it turns out that not everyone wants to know.
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(Laughter)
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But I'm guessing that many of you do,
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and so I brought some kits here if you're interested
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in trying this out for yourself.
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So why might we want to do this?
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Well, it turns out that microbes are not just important
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for finding out where we are in terms of our health,
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but they can actually cure disease.
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This is one of the newest things we've been able to visualize
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with colleagues at the University of Minnesota.
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So here's that map of the human microbiome again.
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What we're looking at now --
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I'm going to add in the community of some people with C. diff.
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So, this is a terrible form of diarrhea
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where you have to go up to 20 times a day,
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and these people have failed antibiotic therapy for two years
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before they're eligible for this trial.
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So what would happen if we transplanted some of the stool from a healthy donor,
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that star down at the bottom,
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into these patients.
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Would the good microbes do battle with the bad microbes
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and help to restore their health?
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So let's watch exactly what happens there.
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Four of those patients are about to get a transplant
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from that healthy donor at the bottom,
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and what you can see is that immediately,
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you have this radical change in the gut community.
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So one day after you do that transplant,
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all those symptoms clear up,
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the diarrhea vanishes,
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and they're essentially healthy again, coming to resemble the donor's community,
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and they stay there.
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(Applause)
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So we're just at the beginning of this discovery.
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We're just finding out that microbes have implications
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for all these different kinds of diseases,
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ranging from inflammatory bowel disease to obesity,
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and perhaps even autism and depression.
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What we need to do, though,
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is we need to develop a kind of microbial GPS,
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where we don't just know where we are currently
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but also where we want to go and what we need to do
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in order to get there,
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and we need to be able to make this simple enough
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that even a child can use it. (Laughter)
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Thank you.
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(Applause)
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