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Hello. My name is Richard Losick and I'm a professor at Harvard University.
My presentation today will address the question,
are we more microbial than human?
I'm a microbiologist and I've devoted almost the entirety of my career
to studying a single kind of bacterium that lives in the soil,
but I'm going to tell you today about an exciting new direction
in microbiological research, concerning the myriad microbes
that live in and on our bodies.
These microbes are so tiny that we can't see them with the naked eye,
and hence, we're not aware of their presence,
or of their influence on our health and well-being.
I'm going to give you four examples of how these microbes influence us
in various ways.
First, they contribute on the one hand to obesity,
and on the other hand, to malnutrition.
Secondly, they can stimulate the immune system,
both positively, or in the example I'll give you,
negatively. Third, they can influence the effectiveness of various medicines and drugs
that we ingest.
And then finally, throwing caution to the wind,
I'm going to suggest that these microbes might also influence our behavior.
Normal behavior, and abnormal behavior.
Leonardo da Vinci depicted the male figure in this iconic drawing.
Da Vinci didn't know that now we know
that all living things are composed of cells
and the human body is composed of 10 trillion cells.
Ten trillion is a big number
but it's only ten percent of the 100 trillion bacterial cells
that we humans host in and on our bodies.
Not only that, these bacterial collectively carry 100 times more genes
of different kinds than all of the genes in the human genome.
We have thousands of different species of bacteria in our bodies.
These bacteria share many genes in common,
but they also have, frequently, distinctive genes.
So, if we count up all of the different kinds of genes
that these 100 trillion bacteria have collectively,
they represent substantially more genetic information
than the 20,000 or so genes in the nucleus of our human cells.
These bacteria are found in various parts of our body,
in our ears, in our nasal passages,
on our skin, but I'm going to focus principally on the bacteria found in the gastrointestinal tract,
the gut, that's where the majority of these bacteria are.
Well, how do we study their influence?
It's very hard to do experiments on humans
and it's unethical to do some of the kinds of experiments we might like to do,
but we can do experiments on mice into which we've transferred bacteria
from other mice or from humans themselves.
This is an approach that was pioneered by Jeff Gordon of Washington University,
in which germ-free mice are created that are born and maintained under aseptic conditions,
such that they're entirely lacking bacteria.
And now we can use those mice as a recipient
for introducing bacteria from other kinds of mice,
or from humans, and then look at the effect
of these bacteria on the recipient mouse.
I'm going to begin by giving you two examples
of recent discoveries from the Gordon laboratory
on obesity and malnutrition.
So, let me tell you how gut bacteria can contribute to obesity.
So, this experiment involves a special kind of mouse called the obese mouse.
The obese mouse has a mutation in the ob gene
that blocks the production of a hormone called leptin that inhibits appetite.
So, a mouse that's mutant for both copies of the ob gene
is visibly obese, as you can see, it doesn't make leptin,
appetite is not inhibited, it's considerably larger than its wild-type sibling.
So, the experiment is going to be to take bacteria
from the obese mouse and transfer it into a germ-free mouse recipient,
and take bacteria from a wild-type mouse and transfer those bacteria
into a germ free recipient and look at the effect on increase in body fat.
And that's shown in the next slide.
So, the dark column in this slide
shows the case in which the donor was wild-type mouse,
its bacteria are transferred into the germ-free mouse,
and as you can see, there was an approximately 25 percent increase in body fat.
But, if the donor was an obese mouse,
now, the increase in body fat is up here over 40 percent in body fat.
So, even though the recipient in both cases is a wild-type, ordinary, wild-type mouse,
the composition of the bacteria that it received influences its weight gain and body fat.
Ok, now let me tell you the opposite example.
This involves a disease that's found in certain countries in Africa,
it's a severe form of malnutrition observed in children
and it's called Kwashiorkor.
So, this is a child that's suffering from Kwashiorkor
and the way this experiment was done is that identical twins were identified
in which one child was suffering from Kwashiorkor and the other child wasn't.
And then, bacteria were transferred in what is known as a fecal transplant
into germ-free mice to look at their affect on the recipient.
And the striking result was that mice that received a fecal transplant
from children with Kwashiorkor exhibited a marked weight loss,
whereas mice that received the fecal transplant from the twin
that was not suffering from the disease
did not exhibit this weight loss.
So, the mouse model allows us to see this effect of bacteria,
and this result tells us that this disease has a microbial component,
as well as other kinds of environmental influences that might cause Kwashiorkor disease.
Ok, so, now let me switch to my second example,
which is the immune system.
Gut bacteria contribute to proper development of the immune system,
and sometimes lead to an overstimulation of the immune system.
I'm going to tell you now about experiments once again done with mice
involving a mouse model for a human disease called colitis.
So, in these experiments, certain mutant mice were used
that have a defective immune system, and as a consequence,
their colon becomes inflamed.
We can recognize this colitis condition by what's known as an anorectal prolapse,
on the one hand, or by a thickening of the colon.
So, this is a colon from a mouse with colitis,
and the bar marks the region where the colon is thicker,
as compared to a normal mouse that has, doesn't have this thickening
that we see with the colitis colon.
Ok, well, this condition is caused by bacteria.
How do we know that?
Well, we know that from a simple experiment
in which the mouse are treated with antibiotics.
So, this experiment here measures colitis by using what's known as a histological colitis score.
So, histological simply means that the tissue of the colon
is examined microscopically and assigned a value
given how severe the colitis condition is.
And each of these dots in this graph represent a different mouse
from a separate experiment. If the mice were treated with antibiotics,
as you can see down here, then they're protected from getting colitis.
But if they weren't treated with antibiotics,
as you can see over here,
then they do develop, these mutant mice do develop colitis.
Ok, I may have left you with the impression that all bacteria in the gut
cause this colitis condition. But, actually, it's more complicated than that.
There are certain bacteria that belong to a broad category known as
the enterobacterioceae that lead to this inflammation.
Enterobacterioceae may be a strange word to you,
but the well-known bacterium E. coli that almost everybody has heard of
is a member of this enterobacterioceae group, which causes inflammation
in colitis. But there are also other bacteria that are good bacteria
and an example of that is Bifidobacterium.
Mice that are fed milk that was fermented with Bifidobacterium
get partially protected from developing colitis.
So, you can see that over here,
that this is a case in which the mice were fed this fermented milk,
and their colitis score is lower than in the control case, in which they weren't exposed to Bifidobacterium.
So, enterobacterioceae can, on the one hand,
promote the disease, and another kind of bacterium, can protect against the disease.
These experiments show then, that there is a microbiological component
to the colitis disease.
Now, I want to tell you something that I find particularly astonishing
about this mouse system for studying colitis.
And that is, not only is it caused by bacteria,
but it's become contagious.
And you can see that in this next experiment
in which what we do is to co-house a wild-type mouse
with either another wild-type mouse or with a mutant mouse that has colitis.
Once again, each dot is a different mouse from a different experiment
and you can see that if we take wild-type mice
and co-house them with wild-type mice, nobody gets colitis.
But if we take wild-type mice and they're roommates, their cage-mates,
are the colitis-prone mice, well then, the wild-type mice gets colitis.
So, this tells us that even a wild-type mice can get colitis,
is susceptible to colitis if it gets the right kind of bacteria
into its system, which it can acquire from co-living with a mouse that has the condition.
My third example, now, comes from the effect of our microbes
on the medicines that we take.
So, I'm going to pose the question, do guy bacteria metabolize medicines
and influence their effectiveness?
Well, there's reason to believe that this is true at least for one well-known medicine
called digoxin, which is widely used
to treat individuals with certain kinds of heart disease,
because it slows the heart rate.
So, these are experiments that were done by my colleague at Harvard,
Peter Turnbaugh. Now, the thing about digoxin
is that some individuals need a high dose of the drug, and other individuals need a low dose of the drug
and it's important to get the dosing right
and it's, so it's hard to find out just the right dose for different people.
Why does it vary from patient to patient/
Well, what's emerged is that there is a bacterium in the gut
called Eggerthella lenta that metabolically inactivates digoxin.
Digoxin has this complex structure shown at the bottom
and the E. lenta bacterium can act on this terminal ring
to inactivate it and thereby destroy the effectiveness of the medicine.
So, maybe individuals that need high levels of digoxin
have high levels of this digoxin- destroying bacterium in their gut,
and other individuals that respond to low doses
have low levels of the E. lenta bacterium.
And if this is true, it raises the question about whether gut bacteria
might metabolize other useful medicines.
Now, I don't want to leave you with a view that the bacteria are only doing negative things,
the opposite might be the case.
Might it be the case that gut bacteria inactivate harmful foreign substances
that we ingest, such as carcinogens from that steak that you just roasted on the barbeque
and generated various carcinogens, maybe the bacteria in your gut
are helping to break down those carcinogens before they cause harm
in your body. Ok. Let me now shift to my last example which is, as I said,
a case where I'm going to go way out on a limb
and suggest that maybe these bacteria also influencing our behavior.
I suggest that because, first of all, bacteria are master chemists,
they make many, many different kinds of small molecules,
they are really good at this,
they use those molecules to communicate with each other,
and possibly with their human hosts.
Also, they've co-evolved with us for eons.
So, is it possible that the bacteria that we carry around with us
produce neurologically active compounds that influence our behavior,
both normal behavior as well as psychiatric disorders?
Do these bacteria stimulate us to eat certain foods that we shouldn't eat
for their benefit, and not for our benefit?
Who knows? Well, I'm going to tell you about one experiment,
once again using mouse model,
that hints that maybe something like this could be going on.
People who study behavior in mice have a technique for measuring anxiety
and risk taking and for this they use a device which is a kind of elevated platform
that has two arms. Now, these arms here have side walls,
whereas, the arms that run across don't have side walls.
So, if a mouse is feeling anxious, it will stay in the central arms,
whereas, if it's a risk taker, it'll venture out onto these arms that don't have side walls.
Well, the experiment I'm about to tell you
suggests that bacteria-free mice are less anxious and more of risk-taker
than mice with normal gut bacteria.
So, here's the experiment first with a mouse with normal gut bacteria.
It starts out in the arm with central wings, it takes little peek out
into the area where the arms aren't covered, but it ducks back in, as you see,
and conservatively stays in the protective realm of the arm with the side walls,
in fact, is hanging out near one end, where it can feel safe, perhaps.
Now, let's consider a mouse, a similar mouse, except this mouse is one of these germ-free mice
that lacks all the bacteria in its gut.
It starts out in the arm that's enclosed,
it starts exploring around, it takes peek out,
oh, and then it rushes out, in fact it rushes right to the end,
hangs out off the edge, where it's in danger of falling off,
it's a braver mouse than the mouse that has bacteria.
Somehow, the presence of bacteria are influencing the behavior of these mice.
Ok, so, let me return now to the question I began with.
Are we more microbial than human?
We live in intimate association with bacteria
that exceed human cells in number and genetic complexity.
These gut bacteria influence the utilization of food and foreign substances
and stimulate the immune system.
These bacteria produce vast numbers of small molecules
that may influence our well-being and behavior in ways that we have not yet imagined.
I would like to close now by telling you something a little bit amusing.
So, we at Harvard University host an event known as the Ignobel Awards
which is a spoof of the Nobel Prize that's intended to be both humorous and educational
and a few years back, the theme of the Ignobel Awards
was bacteria and I was invited to give the keynote address.
Now, I need to explain, there are very rigid rules about the keynote address.
The speaker is allowed only 60 seconds for his or her entire address.
In addition, and this will become significant in a moment,
there is the threat that if you go over 60 seconds,
a little girl will come on the stage and tug at your sleeve
and announce to the audience that she's bored.
Wow, that's very intimidating.
Ok, I enjoyed speaking with all of you,
and I got out now with this final little clip about the Ignobel Awards
in my keynote address. Thank you very much.
(Moderator) "Keynote speech on the topic bacteria will be given by Richard Losick,
the Harvard College professor and Maria Moores,
Cabot professor of biology at Harvard University,
please welcome, the man and his bacteria, Rich Losick."
RL: Hello! Many of you brought a guest or two this evening!
Or thought you did!
I'm here to tell you that all of you brought a hundred trillion guests.
These are the bacteria that live in our body.
There are ten times more of them than there are human cells in the body.
And they contain a hundred times more genes than all the genes in the human genome.
These bacteria influence whether you're lean or obese.
Whether your immune system is developed properly,
and consider this, they communicate with each other chemically.
And undoubtedly with their human host as well, perhaps influencing our behavior!
Was it your decision to come tonight?
Or was it theirs?
Lastly, let me share with you the secret to health, wealth and happiness,
which is to stay in touch with your inner microbiome.
Can you hear that, Daniel, can you help me?
(eerp, squeak, merp)
Permit me to translate. They're saying, please stop,
we're bored, we're bored! Thank you!