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The Human Microbiome: Are We More Microbial than Human?

00:00:05.27 Hello. My name is Richard Losick and I'm a professor at Harvard University.
00:00:12.15 My presentation today will address the question,
00:00:15.24 are we more microbial than human?
00:00:18.25 I'm a microbiologist and I've devoted almost the entirety of my career
00:00:24.15 to studying a single kind of bacterium that lives in the soil,
00:00:28.09 but I'm going to tell you today about an exciting new direction
00:00:32.06 in microbiological research, concerning the myriad microbes
00:00:36.00 that live in and on our bodies.
00:00:39.00 These microbes are so tiny that we can't see them with the naked eye,
00:00:43.21 and hence, we're not aware of their presence,
00:00:46.20 or of their influence on our health and well-being.
00:00:51.19 I'm going to give you four examples of how these microbes influence us
00:00:57.25 in various ways.
00:01:00.15 First, they contribute on the one hand to obesity,
00:01:05.13 and on the other hand, to malnutrition.
00:01:08.23 Secondly, they can stimulate the immune system,
00:01:12.24 both positively, or in the example I'll give you,
00:01:16.18 negatively. Third, they can influence the effectiveness of various medicines and drugs
00:01:24.19 that we ingest.
00:01:25.29 And then finally, throwing caution to the wind,
00:01:28.17 I'm going to suggest that these microbes might also influence our behavior.
00:01:34.07 Normal behavior, and abnormal behavior.
00:01:37.21 Leonardo da Vinci depicted the male figure in this iconic drawing.
00:01:44.27 Da Vinci didn't know that now we know
00:01:47.25 that all living things are composed of cells
00:01:50.13 and the human body is composed of 10 trillion cells.
00:01:54.25 Ten trillion is a big number
00:01:58.16 but it's only ten percent of the 100 trillion bacterial cells
00:02:03.08 that we humans host in and on our bodies.
00:02:07.10 Not only that, these bacterial collectively carry 100 times more genes
00:02:14.06 of different kinds than all of the genes in the human genome.
00:02:17.24 We have thousands of different species of bacteria in our bodies.
00:02:22.12 These bacteria share many genes in common,
00:02:26.08 but they also have, frequently, distinctive genes.
00:02:29.27 So, if we count up all of the different kinds of genes
00:02:33.23 that these 100 trillion bacteria have collectively,
00:02:38.02 they represent substantially more genetic information
00:02:42.29 than the 20,000 or so genes in the nucleus of our human cells.
00:02:48.27 These bacteria are found in various parts of our body,
00:02:54.11 in our ears, in our nasal passages,
00:02:57.09 on our skin, but I'm going to focus principally on the bacteria found in the gastrointestinal tract,
00:03:06.11 the gut, that's where the majority of these bacteria are.
00:03:09.19 Well, how do we study their influence?
00:03:11.24 It's very hard to do experiments on humans
00:03:15.07 and it's unethical to do some of the kinds of experiments we might like to do,
00:03:19.23 but we can do experiments on mice into which we've transferred bacteria
00:03:24.23 from other mice or from humans themselves.
00:03:29.07 This is an approach that was pioneered by Jeff Gordon of Washington University,
00:03:36.29 in which germ-free mice are created that are born and maintained under aseptic conditions,
00:03:45.09 such that they're entirely lacking bacteria.
00:03:48.08 And now we can use those mice as a recipient
00:03:52.03 for introducing bacteria from other kinds of mice,
00:03:57.05 or from humans, and then look at the effect
00:04:00.11 of these bacteria on the recipient mouse.
00:04:03.28 I'm going to begin by giving you two examples
00:04:09.03 of recent discoveries from the Gordon laboratory
00:04:13.04 on obesity and malnutrition.
00:04:16.24 So, let me tell you how gut bacteria can contribute to obesity.
00:04:21.22 So, this experiment involves a special kind of mouse called the obese mouse.
00:04:28.15 The obese mouse has a mutation in the ob gene
00:04:32.06 that blocks the production of a hormone called leptin that inhibits appetite.
00:04:38.05 So, a mouse that's mutant for both copies of the ob gene
00:04:43.06 is visibly obese, as you can see, it doesn't make leptin,
00:04:47.00 appetite is not inhibited, it's considerably larger than its wild-type sibling.
00:04:52.25 So, the experiment is going to be to take bacteria
00:04:57.18 from the obese mouse and transfer it into a germ-free mouse recipient,
00:05:02.11 and take bacteria from a wild-type mouse and transfer those bacteria
00:05:06.16 into a germ free recipient and look at the effect on increase in body fat.
00:05:11.28 And that's shown in the next slide.
00:05:14.26 So, the dark column in this slide
00:05:16.25 shows the case in which the donor was wild-type mouse,
00:05:21.29 its bacteria are transferred into the germ-free mouse,
00:05:25.15 and as you can see, there was an approximately 25 percent increase in body fat.
00:05:31.15 But, if the donor was an obese mouse,
00:05:34.25 now, the increase in body fat is up here over 40 percent in body fat.
00:05:41.19 So, even though the recipient in both cases is a wild-type, ordinary, wild-type mouse,
00:05:49.00 the composition of the bacteria that it received influences its weight gain and body fat.
00:05:55.25 Ok, now let me tell you the opposite example.
00:06:00.00 This involves a disease that's found in certain countries in Africa,
00:06:06.28 it's a severe form of malnutrition observed in children
00:06:10.22 and it's called Kwashiorkor.
00:06:12.14 So, this is a child that's suffering from Kwashiorkor
00:06:15.26 and the way this experiment was done is that identical twins were identified
00:06:23.01 in which one child was suffering from Kwashiorkor and the other child wasn't.
00:06:29.00 And then, bacteria were transferred in what is known as a fecal transplant
00:06:34.08 into germ-free mice to look at their affect on the recipient.
00:06:38.17 And the striking result was that mice that received a fecal transplant
00:06:42.29 from children with Kwashiorkor exhibited a marked weight loss,
00:06:47.24 whereas mice that received the fecal transplant from the twin
00:06:55.03 that was not suffering from the disease
00:06:57.22 did not exhibit this weight loss.
00:07:00.09 So, the mouse model allows us to see this effect of bacteria,
00:07:05.12 and this result tells us that this disease has a microbial component,
00:07:10.12 as well as other kinds of environmental influences that might cause Kwashiorkor disease.
00:07:17.02 Ok, so, now let me switch to my second example,
00:07:21.00 which is the immune system.
00:07:22.25 Gut bacteria contribute to proper development of the immune system,
00:07:28.04 and sometimes lead to an overstimulation of the immune system.
00:07:33.18 I'm going to tell you now about experiments once again done with mice
00:07:37.25 involving a mouse model for a human disease called colitis.
00:07:43.08 So, in these experiments, certain mutant mice were used
00:07:47.19 that have a defective immune system, and as a consequence,
00:07:51.05 their colon becomes inflamed.
00:07:55.17 We can recognize this colitis condition by what's known as an anorectal prolapse,
00:08:06.02 on the one hand, or by a thickening of the colon.
00:08:09.17 So, this is a colon from a mouse with colitis,
00:08:14.26 and the bar marks the region where the colon is thicker,
00:08:17.22 as compared to a normal mouse that has, doesn't have this thickening
00:08:25.26 that we see with the colitis colon.
00:08:30.05 Ok, well, this condition is caused by bacteria.
00:08:35.14 How do we know that?
00:08:36.23 Well, we know that from a simple experiment
00:08:40.08 in which the mouse are treated with antibiotics.
00:08:43.00 So, this experiment here measures colitis by using what's known as a histological colitis score.
00:08:53.13 So, histological simply means that the tissue of the colon
00:08:59.03 is examined microscopically and assigned a value
00:09:02.16 given how severe the colitis condition is.
00:09:05.21 And each of these dots in this graph represent a different mouse
00:09:10.24 from a separate experiment. If the mice were treated with antibiotics,
00:09:16.03 as you can see down here, then they're protected from getting colitis.
00:09:20.21 But if they weren't treated with antibiotics,
00:09:23.11 as you can see over here,
00:09:25.19 then they do develop, these mutant mice do develop colitis.
00:09:32.06 Ok, I may have left you with the impression that all bacteria in the gut
00:09:39.18 cause this colitis condition. But, actually, it's more complicated than that.
00:09:44.02 There are certain bacteria that belong to a broad category known as
00:09:48.24 the enterobacterioceae that lead to this inflammation.
00:09:54.09 Enterobacterioceae may be a strange word to you,
00:09:59.16 but the well-known bacterium E. coli that almost everybody has heard of
00:10:03.21 is a member of this enterobacterioceae group, which causes inflammation
00:10:09.10 in colitis. But there are also other bacteria that are good bacteria
00:10:14.00 and an example of that is Bifidobacterium.
00:10:17.05 Mice that are fed milk that was fermented with Bifidobacterium
00:10:24.00 get partially protected from developing colitis.
00:10:27.08 So, you can see that over here,
00:10:29.25 that this is a case in which the mice were fed this fermented milk,
00:10:33.25 and their colitis score is lower than in the control case, in which they weren't exposed to Bifidobacterium.
00:10:42.08 So, enterobacterioceae can, on the one hand,
00:10:46.19 promote the disease, and another kind of bacterium, can protect against the disease.
00:10:52.27 These experiments show then, that there is a microbiological component
00:11:00.05 to the colitis disease.
00:11:02.26 Now, I want to tell you something that I find particularly astonishing
00:11:07.17 about this mouse system for studying colitis.
00:11:11.00 And that is, not only is it caused by bacteria,
00:11:14.14 but it's become contagious.
00:11:16.17 And you can see that in this next experiment
00:11:21.04 in which what we do is to co-house a wild-type mouse
00:11:27.00 with either another wild-type mouse or with a mutant mouse that has colitis.
00:11:33.23 Once again, each dot is a different mouse from a different experiment
00:11:37.04 and you can see that if we take wild-type mice
00:11:41.18 and co-house them with wild-type mice, nobody gets colitis.
00:11:46.07 But if we take wild-type mice and they're roommates, their cage-mates,
00:11:52.29 are the colitis-prone mice, well then, the wild-type mice gets colitis.
00:11:58.15 So, this tells us that even a wild-type mice can get colitis,
00:12:05.23 is susceptible to colitis if it gets the right kind of bacteria
00:12:10.09 into its system, which it can acquire from co-living with a mouse that has the condition.
00:12:20.11 My third example, now, comes from the effect of our microbes
00:12:27.16 on the medicines that we take.
00:12:30.05 So, I'm going to pose the question, do guy bacteria metabolize medicines
00:12:36.10 and influence their effectiveness?
00:12:38.23 Well, there's reason to believe that this is true at least for one well-known medicine
00:12:46.03 called digoxin, which is widely used
00:12:48.22 to treat individuals with certain kinds of heart disease,
00:12:53.14 because it slows the heart rate.
00:12:55.22 So, these are experiments that were done by my colleague at Harvard,
00:12:59.11 Peter Turnbaugh. Now, the thing about digoxin
00:13:03.00 is that some individuals need a high dose of the drug, and other individuals need a low dose of the drug
00:13:09.19 and it's important to get the dosing right
00:13:11.26 and it's, so it's hard to find out just the right dose for different people.
00:13:15.11 Why does it vary from patient to patient/
00:13:18.04 Well, what's emerged is that there is a bacterium in the gut
00:13:22.11 called Eggerthella lenta that metabolically inactivates digoxin.
00:13:27.18 Digoxin has this complex structure shown at the bottom
00:13:31.10 and the E. lenta bacterium can act on this terminal ring
00:13:37.06 to inactivate it and thereby destroy the effectiveness of the medicine.
00:13:44.21 So, maybe individuals that need high levels of digoxin
00:13:52.00 have high levels of this digoxin- destroying bacterium in their gut,
00:13:56.22 and other individuals that respond to low doses
00:13:59.22 have low levels of the E. lenta bacterium.
00:14:03.05 And if this is true, it raises the question about whether gut bacteria
00:14:07.14 might metabolize other useful medicines.
00:14:10.22 Now, I don't want to leave you with a view that the bacteria are only doing negative things,
00:14:15.15 the opposite might be the case.
00:14:17.21 Might it be the case that gut bacteria inactivate harmful foreign substances
00:14:24.06 that we ingest, such as carcinogens from that steak that you just roasted on the barbeque
00:14:30.03 and generated various carcinogens, maybe the bacteria in your gut
00:14:34.16 are helping to break down those carcinogens before they cause harm
00:14:38.06 in your body. Ok. Let me now shift to my last example which is, as I said,
00:14:50.11 a case where I'm going to go way out on a limb
00:14:52.27 and suggest that maybe these bacteria also influencing our behavior.
00:14:57.23 I suggest that because, first of all, bacteria are master chemists,
00:15:02.27 they make many, many different kinds of small molecules,
00:15:07.02 they are really good at this,
00:15:08.04 they use those molecules to communicate with each other,
00:15:13.01 and possibly with their human hosts.
00:15:16.07 Also, they've co-evolved with us for eons.
00:15:19.27 So, is it possible that the bacteria that we carry around with us
00:15:23.20 produce neurologically active compounds that influence our behavior,
00:15:28.04 both normal behavior as well as psychiatric disorders?
00:15:32.04 Do these bacteria stimulate us to eat certain foods that we shouldn't eat
00:15:36.18 for their benefit, and not for our benefit?
00:15:39.14 Who knows? Well, I'm going to tell you about one experiment,
00:15:44.13 once again using mouse model,
00:15:46.19 that hints that maybe something like this could be going on.
00:15:50.14 People who study behavior in mice have a technique for measuring anxiety
00:15:58.07 and risk taking and for this they use a device which is a kind of elevated platform
00:16:06.16 that has two arms. Now, these arms here have side walls,
00:16:13.17 whereas, the arms that run across don't have side walls.
00:16:20.05 So, if a mouse is feeling anxious, it will stay in the central arms,
00:16:26.20 whereas, if it's a risk taker, it'll venture out onto these arms that don't have side walls.
00:16:34.05 Well, the experiment I'm about to tell you
00:16:37.17 suggests that bacteria-free mice are less anxious and more of risk-taker
00:16:44.05 than mice with normal gut bacteria.
00:16:46.05 So, here's the experiment first with a mouse with normal gut bacteria.
00:16:53.09 It starts out in the arm with central wings, it takes little peek out
00:16:58.29 into the area where the arms aren't covered, but it ducks back in, as you see,
00:17:05.22 and conservatively stays in the protective realm of the arm with the side walls,
00:17:12.12 in fact, is hanging out near one end, where it can feel safe, perhaps.
00:17:18.18 Now, let's consider a mouse, a similar mouse, except this mouse is one of these germ-free mice
00:17:26.10 that lacks all the bacteria in its gut.
00:17:28.26 It starts out in the arm that's enclosed,
00:17:33.27 it starts exploring around, it takes peek out,
00:17:40.07 oh, and then it rushes out, in fact it rushes right to the end,
00:17:44.07 hangs out off the edge, where it's in danger of falling off,
00:17:47.19 it's a braver mouse than the mouse that has bacteria.
00:17:54.08 Somehow, the presence of bacteria are influencing the behavior of these mice.
00:18:01.08 Ok, so, let me return now to the question I began with.
00:18:06.13 Are we more microbial than human?
00:18:08.17 We live in intimate association with bacteria
00:18:12.10 that exceed human cells in number and genetic complexity.
00:18:17.02 These gut bacteria influence the utilization of food and foreign substances
00:18:22.18 and stimulate the immune system.
00:18:24.28 These bacteria produce vast numbers of small molecules
00:18:28.08 that may influence our well-being and behavior in ways that we have not yet imagined.
00:18:34.09 I would like to close now by telling you something a little bit amusing.
00:18:41.08 So, we at Harvard University host an event known as the Ignobel Awards
00:18:47.16 which is a spoof of the Nobel Prize that's intended to be both humorous and educational
00:18:54.20 and a few years back, the theme of the Ignobel Awards
00:18:59.10 was bacteria and I was invited to give the keynote address.
00:19:03.05 Now, I need to explain, there are very rigid rules about the keynote address.
00:19:07.19 The speaker is allowed only 60 seconds for his or her entire address.
00:19:14.04 In addition, and this will become significant in a moment,
00:19:17.10 there is the threat that if you go over 60 seconds,
00:19:21.02 a little girl will come on the stage and tug at your sleeve
00:19:24.20 and announce to the audience that she's bored.
00:19:28.17 Wow, that's very intimidating.
00:19:31.05 Ok, I enjoyed speaking with all of you,
00:19:35.20 and I got out now with this final little clip about the Ignobel Awards
00:19:41.15 in my keynote address. Thank you very much.
00:19:43.29 (Moderator) "Keynote speech on the topic bacteria will be given by Richard Losick,
00:19:51.16 the Harvard College professor and Maria Moores,
00:19:53.21 Cabot professor of biology at Harvard University,
00:19:56.10 please welcome, the man and his bacteria, Rich Losick."
00:20:00.21 RL: Hello! Many of you brought a guest or two this evening!
00:20:09.29 Or thought you did!
00:20:11.16 I'm here to tell you that all of you brought a hundred trillion guests.
00:20:16.11 These are the bacteria that live in our body.
00:20:20.18 There are ten times more of them than there are human cells in the body.
00:20:25.17 And they contain a hundred times more genes than all the genes in the human genome.
00:20:31.16 These bacteria influence whether you're lean or obese.
00:20:35.20 Whether your immune system is developed properly,
00:20:38.20 and consider this, they communicate with each other chemically.
00:20:42.25 And undoubtedly with their human host as well, perhaps influencing our behavior!
00:20:48.21 Was it your decision to come tonight?
00:20:50.25 Or was it theirs?
00:20:52.11 Lastly, let me share with you the secret to health, wealth and happiness,
00:20:59.00 which is to stay in touch with your inner microbiome.
00:21:05.18 Can you hear that, Daniel, can you help me?
00:21:09.11 (eerp, squeak, merp)
00:21:12.20 Permit me to translate. They're saying, please stop,
00:21:20.17 we're bored, we're bored! Thank you!

This Talk
Speaker: Richard Losick
Audience:
  • Educators of H. School / Intro Undergrad
  • Educators of Adv. Undergrad / Grad
  • Researcher
  • Educators
Recorded: July 2013
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Talk Overview

Losick poses the question “Are we more microbial than human?”  There are 10 times more bacterial cells on and in us, the human microbiome, than human cells and 100 times more types of bacterial genes than human genes.  These bacteria certainly influence our health, and Losick wonders if they also might influence our behavior.

Speaker Bio

Richard Losick

Richard Losick

Richard Losick is a Howard Hughes Medical Institute Professor, the Maria Moors Cabot Professor of Biology, and a Harvard College Professor. He received his B.A. from Princeton University in 1965 and his Ph.D. from MIT in 1969. He was elected to the Harvard Society of Fellows as a Junior Fellow in 1969, and he joined… Continue Reading

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