Microbes: How our microbes make us who we are

“The three pounds of microbes that you carry around with you might be more important than every single gene you carry around in your genome, he says…. Today, we can tell whether you’re lean or obese with 90 percent accuracy by looking at the microbes in your gut. Find out why.”

Microbes

Microbes

Video Transcript

0:13We humans have always been very concerned about the health of our bodies,

0:17but we haven’t always been that good at figuring out what’s important.

0:21Take the ancient Egyptians, for example:

0:23very concerned about the body parts they thought they’d need in the afterlife,

0:27but they left some parts out.

0:29This part, for example.

0:32Although they very carefully preserved the stomach, the lungs,

0:35the liver, and so forth,

0:36they just mushed up the brain, drained it out through the nose,

0:39and threw it away,

0:41which makes sense, really,

0:42because what does a brain do for us anyway?

0:45But imagine if there were a kind of neglected organ in our bodies

0:48that weighed just as much as the brain

0:50and in some ways was just as important to who we are,

0:53but we knew so little about and treated with such disregard.

0:57And imagine if, through new scientific advances,

1:00we were just beginning to understand

1:01its importance to how we think of ourselves.

1:04Wouldn’t you want to know more about it?

1:07Well, it turns out that we do have something just like that:

1:10our gut,

1:12or rather, its microbes.

1:15But it’s not just the microbes in our gut that are important.

1:18Microbes all over our body

1:19turn out to be really critical to a whole range of differences

1:22that make different people who we are.

1:25So for example, have you ever noticed

1:27how some people get bitten by mosquitos way more often than others?

1:31It turns out that everyone’s anecdotal experience out camping is actually true.

1:36For example, I seldom get bitten by mosquitos,

1:38but my partner Amanda attracts them in droves,

1:41and the reason why is that we have different microbes on our skin

1:44that produce different chemicals that the mosquitos detect.

1:48Now, microbes are also really important in the field of medicine.

1:51So, for example, what microbes you have in your gut

1:54determine whether particular painkillers are toxic to your liver.

1:58They also determine whether or not other drugs will work for your heart condition.

2:02And, if you’re a fruit fly, at least,

2:05your microbes determine who you want to have sex with.

2:08We haven’t demonstrated this in humans yet

2:10but maybe it’s just a matter of time before we find out. (Laughter)

2:15So microbes are performing a huge range of functions.

2:17They help us digest our food.

2:19They help educate our immune system.

2:21They help us resist disease,

2:23and they may even be affecting our behavior.

2:26So what would a map of all these microbial communities look like?

2:30Well, it wouldn’t look exactly like this,

2:32but it’s a helpful guide for understanding biodiversity.

2:35Different parts of the world have different landscapes of organisms

2:39that are immediately characteristic of one place or another

2:43or another.

2:45With microbiology, it’s kind of the same, although I’ve got to be honest with you:

2:49All the microbes essentially look the same under a microscope.

2:52So instead of trying to identify them visually,

2:55what we do is we look at their DNA sequences,

2:57and in a project called the Human Microbiome Project,

3:00NIH funded this $173 million project

3:04where hundreds of researchers came together

3:06to map out all the A’s, T’s, G’s, and C’s,

3:09and all of these microbes in the human body.

3:11So when we take them together, they look like this.

3:14It’s a bit more difficult to tell who lives where now, isn’t it?

3:18What my lab does is develop computational techniques that allow us

3:22to take all these terabytes of sequence data

3:24and turn them into something that’s a bit more useful as a map,

3:27and so when we do that with the human microbiome data

3:30from 250 healthy volunteers,

3:32it looks like this.

3:35Each point here represents all the complex microbes

3:38in an entire microbial community.

3:40See, I told you they basically all look the same.

3:43So what we’re looking at is each point represents one microbial community

3:46from one body site of one healthy volunteer.

3:49And so you can see that there’s different parts of the map in different colors,

3:53almost like separate continents.

3:54And what it turns out to be

3:56is that those, as the different regions of the body,

3:58have very different microbes in them.

4:00So what we have is we have the oral community up there in green.

4:04Over on the other side, we have the skin community in blue,

4:07the vaginal community in purple,

4:09and then right down at the bottom, we have the fecal community in brown.

4:13And we’ve just over the last few years

4:15found out that the microbes in different parts of the body

4:18are amazingly different from one another.

4:20So if I look at just one person’s microbes

4:23in the mouth and in the gut,

4:25it turns out that the difference between those two microbial communities

4:28is enormous.

4:30It’s bigger than the difference between the microbes in this reef

4:33and the microbes in this prairie.

4:36So this is incredible when you think about it.

4:38What it means is that a few feet of difference in the human body

4:42makes more of a difference to your microbial ecology

4:44than hundreds of miles on Earth.

4:46And this is not to say that two people look basically the same

4:49in the same body habitat, either.

4:51So you probably heard

4:53that we’re pretty much all the same in terms of our human DNA.

4:56You’re 99.99 percent identical in terms of your human DNA

5:00to the person sitting next to you.

5:02But that’s not true of your gut microbes:

5:04you might only share 10 percent similarity

5:07with the person sitting next to you in terms of your gut microbes.

5:10So that’s as different as the bacteria on this prairie

5:13and the bacteria in this forest.

5:16So these different microbes

5:17have all these different kinds of functions that I told you about,

5:21everything from digesting food

5:22to involvement in different kinds of diseases,

5:25metabolizing drugs, and so forth.

5:27So how do they do all this stuff?

5:29Well, in part it’s because

5:31although there’s just three pounds of those microbes in our gut,

5:34they really outnumber us.

5:36And so how much do they outnumber us?

5:38Well, it depends on what you think of as our bodies.

5:41Is it our cells?

5:43Well, each of us consists of about 10 trillion human cells,

5:46but we harbor as many as 100 trillion microbial cells.

5:49So they outnumber us 10 to one.

5:52Now, you might think, well, we’re human because of our DNA,

5:56but it turns out that each of us has about 20,000 human genes,

5:59depending on what you count exactly,

6:01but as many as two million to 20 million microbial genes.

6:06So whichever way we look at it, we’re vastly outnumbered

6:08by our microbial symbionts.

6:11And it turns out that in addition to traces of our human DNA,

6:15we also leave traces of our microbial DNA

6:17on everything we touch.

6:19We showed in a study a few years ago

6:20that you can actually match the palm of someone’s hand up

6:23to the computer mouse that they use routinely

6:25with up to 95 percent accuracy.

6:28So this came out in a scientific journal a few years ago,

6:31but more importantly, it was featured on “CSI: Miami,”

6:33so you really know it’s true.

6:35(Laughter)

6:36So where do our microbes come from in the first place?

6:40Well if, as I do, you have dogs or kids,

6:43you probably have some dark suspicions about that,

6:45all of which are true, by the way.

6:47So just like we can match you to your computer equipment

6:50by the microbes you share,

6:51we can also match you up to your dog.

6:54But it turns out that in adults,

6:56microbial communities are relatively stable,

6:58so even if you live together with someone,

7:00you’ll maintain your separate microbial identity

7:02over a period of weeks, months, even years.

7:05It turns out that our first microbial communities

7:08depend a lot on how we’re born.

7:11So babies that come out the regular way,

7:13all of their microbes are basically like the vaginal community,

7:16whereas babies that are delivered by C-section,

7:18all of their microbes instead look like skin.

7:21And this might be associated with some of the differences

7:24in health associated with Cesarean birth,

7:27such as more asthma, more allergies, even more obesity,

7:30all of which have been linked to microbes now,

7:33and when you think about it, until recently, every surviving mammal

7:37had been delivered by the birth canal,

7:39and so the lack of those protective microbes

7:41that we’ve co-evolved with might be really important

7:44for a lot of these different conditions that we now know involve the microbiome.

7:48When my own daughter was born a couple of years ago

7:51by emergency C-section,

7:53we took matters into our own hands

7:55and made sure she was coated with those vaginal microbes

7:58that she would have gotten naturally.

8:00Now, it’s really difficult to tell whether this has had an effect

8:03on her health specifically, right?

8:05With a sample size of just one child, no matter how much we love her,

8:09you don’t really have enough of a sample size

8:11to figure out what happens on average,

8:13but at two years old, she hasn’t had an ear infection yet,

8:16so we’re keeping our fingers crossed on that one.

8:18And what’s more, we’re starting to do clinical trials with more children

8:22to figure out whether this has a protective effect generally.

8:27So how we’re born has a tremendous effect on what microbes we have initially,

8:32but where do we go after that?

8:34What I’m showing you again here is this map

8:36of the Human Microbiome Project Data,

8:38so each point represents a sample from one body site

8:41from one of 250 healthy adults.

8:43And you’ve seen children develop physically.

8:45You’ve seen them develop mentally.

8:47Now, for the first time, you’re going to see

8:50one of my colleague’s children develop microbially.

8:53So what we are going to look at

8:54is we’re going to look at this one baby’s stool,

8:57the fecal community, which represents the gut,

9:00sampled every week for almost two and a half years.

9:03And so we’re starting on day one.

9:04What’s going to happen is that the infant is going to start off as this yellow dot,

9:08and you can see that he’s starting off basically in the vaginal community,

9:12as we would expect from his delivery mode.

9:14And what’s going to happen over these two and a half years

9:17is that he’s going to travel all the way down

9:19to resemble the adult fecal community from healthy volunteers down at the bottom.

9:23So I’m just going to start this going and we’ll see how that happens.

9:26What you can see, and remember each step in this is just one week,

9:30what you can see is that week to week,

9:32the change in the microbial community of the feces of this one child,

9:37the differences week to week are much greater

9:40than the differences between individual healthy adults

9:42in the Human Microbiome Project cohort,

9:44which are those brown dots down at the bottom.

9:47And you can see he’s starting to approach the adult fecal community.

9:50This is up to about two years.

9:51But something amazing is about to happen here.

9:53So he’s getting antibiotics for an ear infection.

9:56What you can see is this huge change in the community,

9:59followed by a relatively rapid recovery.

10:01I’ll just rewind that for you.

10:05And what we can see is that just over these few weeks,

10:08we have a much more radical change,

10:10a setback of many months of normal development,

10:13followed by a relatively rapid recovery,

10:15and by the time he reaches day 838,

10:19which is the end of this video,

10:21you can see that he has essentially reached the healthy adult stool community,

10:25despite that antibiotic intervention.

10:27So this is really interesting because it raises fundamental questions

10:30about what happens when we intervene at different ages in a child’s life.

10:35So does what we do early on, where the microbiome is changing so rapidly,

10:38actually matter,

10:39or is it like throwing a stone into a stormy sea,

10:42where the ripples will just be lost?

10:45Well, fascinatingly, it turns out that if you give children antibiotics

10:49in the first six months of life,

10:50they’re more likely to become obese later on

10:53than if they don’t get antibiotics then or only get them later,

10:56and so what we do early on may have profound impacts

10:59on the gut microbial community and on later health

11:03that we’re only beginning to understand.

11:05So this is fascinating, because one day, in addition to the effects

11:09that antibiotics have on antibiotic-resistant bacteria,

11:12which are very important,

11:14they may also be degrading our gut microbial ecosystems,

11:17and so one day we may come to regard antibiotics with the same horror

11:20that we currently reserve for those metal tools

11:22that the Egyptians used to use to mush up the brains

11:25before they drained them out for embalming.

11:27So I mentioned that microbes have all these important functions,

11:30and they’ve also now, just over the past few years,

11:32been connected to a whole range of different diseases,

11:35including inflammatory bowel disease,

11:37heart disease, colon cancer,

11:39and even obesity.

11:41Obesity has a really large effect, as it turns out,

11:44and today, we can tell whether you’re lean or obese

11:46with 90 percent accuracy

11:48by looking at the microbes in your gut.

11:50Now, although that might sound impressive,

11:52in some ways it’s a little bit problematic as a medical test,

11:56because you can probably tell which of these people is obese

11:59without knowing anything about their gut microbes,

12:01but it turns out that even if we sequence their complete genomes

12:04and had all their human DNA,

12:06we could only predict which one was obese with about 60 percent accuracy.

12:10So that’s amazing, right?

12:12What it means that the three pounds of microbes that you carry around with you

12:16may be more important for some health conditions

12:18than every single gene in your genome.

12:23And then in mice, we can do a lot more.

12:25So in mice, microbes have been linked to all kinds of additional conditions,

12:29including things like multiple sclerosis,

12:32depression, autism, and again, obesity.

12:35But how can we tell whether these microbial differences

12:38that correlate with disease are cause or effect?

12:41Well, one thing we can do is we can raise some mice

12:44without any microbes of their own in a germ-free bubble.

12:46Then we can add in some microbes that we think are important,

12:49and see what happens.

12:51When we take the microbes from an obese mouse

12:54and transplant them into a genetically normal mouse

12:56that’s been raised in a bubble with no microbes of its own,

12:59it becomes fatter than if it got them from a regular mouse.

13:04Why this happens is absolutely amazing, though.

13:06Sometimes what’s going on is that the microbes

13:08are helping them digest food more efficiently from the same diet,

13:11so they’re taking more energy from their food,

13:13but other times, the microbes are actually affecting their behavior.

13:17What they’re doing is they’re eating more than the normal mouse,

13:20so they only get fat if we let them eat as much as they want.

13:24So this is really remarkable, right?

13:27The implication is that microbes can affect mammalian behavior.

13:33So you might be wondering whether we can also do this sort of thing across species,

13:37and it turns out that if you take microbes from an obese person

13:40and transplant them into mice you’ve raised germ-free,

13:43those mice will also become fatter

13:45than if they received the microbes from a lean person,

13:48but we can design a microbial community that we inoculate them with

13:52that prevents them from gaining this weight.

13:55We can also do this for malnutrition.

13:57So in a project funded by the Gates Foundation,

14:00what we’re looking at is children in Malawi

14:02who have kwashiorkor, a profound form of malnutrition,

14:05and mice that get the kwashiorkor community transplanted into them

14:08lose 30 percent of their body mass

14:11in just three weeks,

14:12but we can restore their health by using the same peanut butter-based supplement

14:16that is used for the children in the clinic,

14:18and the mice that receive the community

14:19from the healthy identical twins of the kwashiorkor children do fine.

14:24This is truly amazing because it suggests that we can pilot therapies

14:27by trying them out in a whole bunch of different mice

14:30with individual people’s gut communities

14:32and perhaps tailor those therapies all the way down to the individual level.

14:38So I think it’s really important that everyone has a chance

14:41to participate in this discovery.

14:43So, a couple of years ago,

14:45we started this project called American Gut,

14:47which allows you to claim a place for yourself on this microbial map.

14:51This is now the largest crowd-funded science project that we know of —

14:54over 8,000 people have signed up at this point.

14:57What happens is, they send in their samples,

15:00we sequence the DNA of their microbes and then release the results back to them.

15:04We also release them, de-identified, to scientists, to educators,

15:07to interested members of the general public, and so forth,

15:10so anyone can have access to the data.

15:13On the other hand,

15:15when we do tours of our lab at the BioFrontiers Institute,

15:18and we explain that we use robots and lasers to look at poop,

15:21it turns out that not everyone wants to know.

15:25(Laughter)

15:26But I’m guessing that many of you do,

15:28and so I brought some kits here if you’re interested

15:30in trying this out for yourself.

15:35So why might we want to do this?

15:36Well, it turns out that microbes are not just important

15:39for finding out where we are in terms of our health,

15:42but they can actually cure disease.

15:44This is one of the newest things we’ve been able to visualize

15:47with colleagues at the University of Minnesota.

15:50So here’s that map of the human microbiome again.

15:53What we’re looking at now —

15:54I’m going to add in the community of some people with C. diff.

15:57So, this is a terrible form of diarrhea

16:00where you have to go up to 20 times a day,

16:02and these people have failed antibiotic therapy for two years

16:05before they’re eligible for this trial.

16:08So what would happen if we transplanted some of the stool from a healthy donor,

16:12that star down at the bottom,

16:14into these patients.

16:15Would the good microbes do battle with the bad microbes

16:18and help to restore their health?

16:20So let’s watch exactly what happens there.

16:22Four of those patients are about to get a transplant

16:25from that healthy donor at the bottom,

16:27and what you can see is that immediately,

16:29you have this radical change in the gut community.

16:31So one day after you do that transplant,

16:33all those symptoms clear up,

16:35the diarrhea vanishes,

16:36and they’re essentially healthy again, coming to resemble the donor’s community,

16:40and they stay there.

16:42(Applause)

16:49So we’re just at the beginning of this discovery.

16:51We’re just finding out that microbes have implications

16:54for all these different kinds of diseases,

16:56ranging from inflammatory bowel disease to obesity,

16:58and perhaps even autism and depression.

17:01What we need to do, though,

17:03is we need to develop a kind of microbial GPS,

17:05where we don’t just know where we are currently

17:07but also where we want to go and what we need to do

17:11in order to get there,

17:12and we need to be able to make this simple enough

17:15that even a child can use it. (Laughter)

17:17Thank you.

17:20(Applause)