Session 9: Coevolution

Transcript of Part 1: Living Together: The Symbiosis of Host-Microbial Interactions

00:00:08.00	My name is Margaret McFall-Ngai
00:00:09.14	and I'm a professor
00:00:11.14	and the Director of the Pacific Biosciences Research Center,
00:00:13.14	School of Ocean and Earth Science and Technology,
00:00:16.07	the University of Hawaii at Manoa.
00:00:18.12	I'd like to start my lecture here
00:00:19.28	with thanking the iBiology team
00:00:21.22	for this opportunity to speak to you today
00:00:24.24	about the field of symbiosis.
00:00:27.12	So, the field of symbiosis is about living together
00:00:29.22	-- it's host-microbial interactions
00:00:32.15	that I will be talking about specifically today.
00:00:34.27	And there's a bit of a revolution in biology.
00:00:38.23	Symbiosis and host-microbial interactions
00:00:41.09	are taking center stage in biology.
00:00:46.11	And I'm going to talk to you today about why this is happening now
00:00:49.04	and exactly why we're sort of in the center of a revolution.
00:00:52.09	So, I'm going to start by talking about
00:00:54.20	the words that we use to describe symbiosis.
00:00:57.11	So, this person right here is
00:00:59.29	Heinrich Anton de Bary
00:01:02.16	and this particular person
00:01:04.25	lived in the 19th century,
00:01:07.04	and at the end of the 19th century
00:01:08.15	he coined the term symbiosis.
00:01:11.21	And the definition that he gave to this term
00:01:13.24	was the living together of unlike organisms.
00:01:16.23	And this particular definition of symbiosis
00:01:21.00	has remained with the field
00:01:22.19	until the present day
00:01:24.20	-- it's a very, very, very general way,
00:01:27.18	but very useful way
00:01:29.24	to think about this particular phenomenon in biology.
00:01:34.00	So, that said,
00:01:37.07	symbiosis is a bit of a catch-all term
00:01:39.05	with no information
00:01:40.19	concerning the effect of fitness.
00:01:42.22	So, what I'm showing up here is
00:01:45.06	I'm showing a very classic symbiosis
00:01:46.21	that a lot of people know of
00:01:49.28	and a lot of people think about,
00:01:51.18	and this is the symbiosis between
00:01:53.09	a clownfish and an anemone,
00:01:55.08	and they live together, persistently,
00:01:57.19	for much of their lives,
00:01:59.07	and it's a classic symbiosis
00:02:01.27	that you can think about.
00:02:03.00	But like I said, the word itself
00:02:05.05	confers no... no...
00:02:09.22	it's a catch-all word with no information
00:02:11.22	concerning the effect on the fitness
00:02:13.19	of either partner.
00:02:14.28	And so first I want to describe
00:02:17.18	what fitness means.
00:02:18.20	So, fitness is an individual's reproductive success,
00:02:23.10	and that is the number of offspring
00:02:25.10	that an individual leaves to the next generation.
00:02:28.06	And so let's think about this idea
00:02:32.14	in terms of symbiosis.
00:02:33.23	So, when we talk about fitness,
00:02:35.23	when we're talking about symbiosis,
00:02:37.14	I think there are...
00:02:39.02	I'm going to consider that there are two partners
00:02:41.03	-- there's symbiont #1 and symbiont #2 --
00:02:42.17	and in a mutualism,
00:02:44.25	which is one of the types of symbiosis,
00:02:46.17	both partners will benefit,
00:02:49.12	and what that means is that both partners
00:02:51.07	will have more in the successive generations
00:02:57.02	from being a partner with the other.
00:02:58.11	And so in the case of the clownfish
00:03:00.17	and the anemone,
00:03:02.03	the clownfish gets a very safe place to live,
00:03:04.07	because the tentacles of the anemone
00:03:06.03	are harmful to other animals;
00:03:07.20	the fish, the clownfish,
00:03:10.28	has learned ways to avoid the danger
00:03:13.08	of living in the tentacles of this anemone;
00:03:15.23	and the anemone gains from having the fish there
00:03:20.25	because the fish releases ammonia
00:03:22.17	that is taken up by the anemone
00:03:24.16	and it's used in the energy production
00:03:28.01	of the anemone.
00:03:30.27	So, this is a true mutualism.
00:03:32.24	The next type of symbiosis I'm going to consider is commensalism.
00:03:36.13	In a commensalism,
00:03:38.14	one partner benefits and one partner is unharmed
00:03:41.19	-- there's no change in the fitness,
00:03:43.25	no change in the reproductive fitness.
00:03:46.29	So, what I'm showing here
00:03:48.25	is another example and this example, here,
00:03:51.05	is the shark/pilot fish example,
00:03:54.21	and in this particular case
00:03:58.15	what happens is is
00:04:01.25	the shark is a messy eater
00:04:03.21	and he eats fish and all sorts of various things
00:04:07.11	and food is released around him
00:04:10.20	and the pilot fish that are associating with the shark
00:04:14.24	take advantage of the fact that the shark is a messy eater.
00:04:18.22	In this case, the pilot fish
00:04:22.01	gained from living with the shark,
00:04:23.12	but it seems to have no effect on the shark.
00:04:26.02	And so in this case, it's very likely that
00:04:28.07	the pilot fish will leave more to the next generation
00:04:30.07	from living with the shark,
00:04:32.10	but the shark...
00:04:34.05	it won't affect the shark's fitness whatsoever.
00:04:36.05	The third example that I'm going to give
00:04:38.28	is the example of parasitism.
00:04:40.26	So, these are the three major types of symbiosis,
00:04:42.27	and in parasitism what happens is
00:04:46.15	one partner benefits and one partner is harmed.
00:04:48.22	So, I'm showing down here a tree,
00:04:51.10	and this particular tree trunk
00:04:53.28	has a large gall on it,
00:04:56.07	and the large gall is present
00:04:59.19	because there is a pathogen that is living,
00:05:05.00	a microbial pathogen is living inside this gall
00:05:06.04	and has created this large gall on this tree.
00:05:11.00	Now, the pathogen, that microorganism that's living in that gall,
00:05:14.06	benefits from living...
00:05:15.23	from parasitizing this tree.
00:05:17.29	The tree on the other hand
00:05:19.25	is harmed by this association,
00:05:21.10	so this is a classic parasitism.
00:05:23.24	So, one of the things I should mention is that
00:05:26.05	as the field has grown,
00:05:27.26	there's a little bit of misuse of these terms,
00:05:32.04	and this is one of the reasons
00:05:34.11	why I wanted to bring this up.
00:05:35.25	The term commensalism
00:05:38.22	is often used by the biomedical community,
00:05:40.13	in my mind and the mind of a lot of people who study symbiosis,
00:05:43.26	incorrectly.
00:05:45.07	And what they'll say is that
00:05:48.29	the microbes in your gut,
00:05:50.14	which I'm going to talk about a little bit...
00:05:51.24	the microbes in your gut are commensal,
00:05:54.11	and what this means is that
00:05:56.19	they have no effect on the host
00:05:58.24	-- they're benefiting but have no effect on the host.
00:06:01.14	But now we know that
00:06:03.29	they have a tremendous effect on the host
00:06:05.22	and are very often very important for our health,
00:06:10.01	and beneficial.
00:06:11.14	There are some in there that are likely commensal,
00:06:12.25	there are some in there that are likely
00:06:15.01	budding pathogens,
00:06:16.17	there are some in there that are likely,
00:06:18.00	or many in there, that are likely mutualists,
00:06:19.25	but we really can't categorize them,
00:06:22.14	so the very best thing to do in the instance
00:06:25.04	where you really don't understand
00:06:27.07	what type of symbiosis it is
00:06:29.19	is to just call it a symbiosis
00:06:31.19	and to call the partners a symbiont.
00:06:34.11	So, let's consider for a second
00:06:37.13	host-microbe symbioses.
00:06:38.29	So, what we're talking about is we're talking about
00:06:41.11	viruses, bacteria, protists
00:06:43.13	-- or single-celled eukaryotic cells --
00:06:45.02	and fungi, living with animals and plants, basically.
00:06:48.18	So, the question is,
00:06:51.02	is this a rarity?
00:06:52.21	And I have to say that when I started my career
00:06:54.09	working in this field,
00:06:56.23	back in the early 1980s,
00:06:58.12	this was considered a very unusual feature of symbiosis...
00:07:02.20	symbiosis was considered an unusual feature
00:07:04.19	in the biological world.
00:07:06.16	And in fact, if you look at a textbook,
00:07:09.03	even today,
00:07:11.00	you will see that symbiosis is covered,
00:07:13.16	but it's covered in only a few pages
00:07:15.10	of a 1200-page textbook.
00:07:17.13	It was and is today still considered a rarity,
00:07:20.15	but I hope you convince you that
00:07:23.00	it's not a rarity at all.
00:07:24.26	But why was it considered a rarity?
00:07:26.26	Well, we would find it...
00:07:28.29	historically, we were looking at
00:07:31.01	unusual situations in things like
00:07:34.14	the hydrothermal vent symbioses in the deep sea.
00:07:38.10	Down at 2000 meters, you know,
00:07:39.21	you see these smokers down at 2000 meters,
00:07:42.01	and these particular smokers
00:07:44.11	would have associated with them
00:07:46.16	these very large tube worms,
00:07:49.00	and these large tube worms
00:07:51.01	had in association with them,
00:07:53.29	bacteria, and these bacteria
00:07:55.28	allowed these particular tube worms
00:07:57.27	to live on the chemical energy
00:08:00.12	that was provided.
00:08:02.02	So that was a true symbiosis
00:08:04.16	that's been studied by lots and lots of people.
00:08:10.01	Bioluminescence is another kind of symbiosis
00:08:14.13	and very many organisms who are bioluminescent,
00:08:17.16	not all, but many organisms that are bioluminescent,
00:08:20.05	are bioluminescent because they harbor
00:08:22.18	luminous bacteria in association with the organism.
00:08:27.04	So, in the case of this anglerfish,
00:08:28.12	up here in the angle
00:08:30.15	is a pure culture of a particular bacterial species,
00:08:33.26	and that allows the anglerfish
00:08:36.21	to use that light in its predation.
00:08:40.09	And then, lastly,
00:08:42.10	I'm going to give the example of coral reefs.
00:08:44.24	Coral reefs would not form
00:08:47.04	if they did not have a very...
00:08:49.17	a mutualistic symbiosis
00:08:51.04	with a unicellular organism called
00:08:53.29	zooxanthellae.
00:08:55.06	And these zooxanthellae live inside of the cells of corals
00:08:58.03	and they provide them with the photosynthate.
00:09:00.29	So, these zooxanthellae
00:09:06.03	are capable of photosynthesis
00:09:08.00	and they translocate the photosynthate to the host.
00:09:10.26	And so the zooxanthellae get a place to live
00:09:14.02	and the host coral is given the photosynthate,
00:09:18.27	and so they both benefit.
00:09:20.07	So, in all the cases I'm showing on this slide,
00:09:22.13	these are mutualistic symbioses,
00:09:24.26	and they're ones that have been
00:09:28.05	studied for over 100 years...
00:09:31.18	actually, not this one,
00:09:33.00	this one they discovered in the late 1970s,
00:09:34.10	but the many, many symbioses
00:09:36.07	that are mutualistic like this,
00:09:38.05	and kind of unusual,
00:09:39.21	have been studied for decades.
00:09:41.12	But now we're finding out that
00:09:43.13	nearly all animals and plants
00:09:45.20	are likely to have beneficial symbioses.
00:09:47.28	So, this is a whole new area,
00:09:51.27	this is a whole new finding,
00:09:53.17	and this new information
00:09:56.23	is from the last two decades of work.
00:09:58.29	And so I'm just showing
00:10:01.25	a whole array of animals
00:10:04.00	that are now known to have
00:10:05.27	beneficial symbioses with microbes.
00:10:10.29	So, I want to just take one minute
00:10:13.10	to pay tribute to what I...
00:10:15.22	the person who I consider
00:10:17.23	the mother of the field of symbiosis,
00:10:19.22	and this is Lynn Margulis.
00:10:21.07	And Lynn Margulis lived 1938-2011,
00:10:23.27	and she was the person
00:10:26.12	who felt that symbiosis was a major driver
00:10:28.17	in the evolution of animals and plants,
00:10:30.19	and she was always way ahead of her time.
00:10:33.20	She became famous f
00:10:35.19	or the endosymbiotic theory
00:10:38.11	of the origin of the eukaryotic cell,
00:10:39.17	and that is to say that bacteria
00:10:41.05	became symbiotic with other bacteria
00:10:43.03	and made a more complex cell.
00:10:45.14	And she showed that at the end of the 1970s,
00:10:50.06	it was very, very controversial,
00:10:52.00	she was way ahead of her time and always was,
00:10:54.09	but she is actually the person
00:10:57.07	who had the vision to say
00:11:00.19	exactly what we're seeing today,
00:11:02.04	and that is that symbiosis
00:11:04.02	is a major thing in biology
00:11:05.16	and has likely been over evolutionary history.
00:11:10.01	So, like I said, nearly all animals and plants
00:11:13.01	are likely to have beneficial symbiosis
00:11:16.05	and this is new information
00:11:18.12	from the last two decades of work.
00:11:20.12	And so what I'm showing here
00:11:22.27	is I'm showing a person,
00:11:24.09	and this person in this artistic rendering
00:11:27.18	is completely covered by microbes.
00:11:30.09	And we are, from the minute we're born,
00:11:34.00	through our life,
00:11:36.25	we associate very intimately with the microbial world.
00:11:39.06	And so we know now that you have as many, if not more,
00:11:42.25	microbial cells than human cells in your body.
00:11:45.04	So, you have about 10^13 human cells
00:11:47.08	and somewhere between 10^13 and 10^14 bacteria
00:11:50.00	that live with you, persistently,
00:11:52.26	your whole life and confer health.
00:11:57.06	So, the question is,
00:11:58.15	why didn't we know about this?
00:12:00.16	Why wasn't this more obvious?
00:12:03.07	Well, it turns out that there was
00:12:05.19	a huge technical problem
00:12:07.06	that we've been able to overcome.
00:12:09.05	And so, the technical problem
00:12:11.02	was a difficulty in identifying
00:12:14.15	and classifying the microorganisms,
00:12:15.17	and why we couldn't do that
00:12:17.15	was because most of these organisms
00:12:19.19	were unculturable under laboratory conditions,
00:12:22.19	and so they're called viable but nonculturable.
00:12:26.00	In other words, they live,
00:12:27.22	but we just can't bring them into the lab
00:12:29.28	and study them the way that we
00:12:33.13	would want to.
00:12:34.18	So, it's about less than 1% of the bacteria
00:12:38.15	that live in association with animals are culturable,
00:12:40.22	so this was a huge technical problem.
00:12:43.12	And so... because
00:12:45.17	we just couldn't know who they were.
00:12:47.10	The other thing was that...
00:12:50.15	another technical problem was that
00:12:53.12	they are relatively featureless.
00:12:55.12	So, what I'm showing here
00:12:57.17	is I'm showing a set of
00:13:00.12	different types of shapes and so on and so forth
00:13:02.27	that you might see
00:13:04.19	in different kinds of bacteria.
00:13:06.00	And so you might compare and contrast that
00:13:10.15	with the morphologies that you see of
00:13:13.09	very, very many plants and animals.
00:13:15.28	I mean, you can really, very well,
00:13:19.12	tell the differences between plants and animals;
00:13:21.21	with microbes, it's not so easy.
00:13:23.25	So, they weren't culturable
00:13:26.08	and you couldn't... they didn't...
00:13:27.26	they were pretty well featureless,
00:13:29.11	so these were big problems.
00:13:31.12	So, even though they're featureless,
00:13:33.06	we began to visualize microorganisms
00:13:36.03	back with Anton van Leeuwenhoek.
00:13:38.06	So, this is Anton van Leeuwenhoek
00:13:40.11	with, you know, several hundred years ago,
00:13:42.08	but he was a guy who
00:13:44.23	developed the very first microscopes,
00:13:47.06	and so he was the first person
00:13:49.26	who allowed us to visualize microorganisms.
00:13:51.16	And what Anton van Leeuwenhoek did was
00:13:54.15	he took a swab
00:13:56.19	and swabbed the inside of his cheek
00:13:58.10	and then he applied that to his microscope,
00:14:01.16	and he was able to see, for the first time,
00:14:05.00	microorganisms.
00:14:06.23	So, not only was he the first person to see microorganisms,
00:14:08.21	but he was the first person to see microorganisms
00:14:10.26	that associate with humans,
00:14:12.08	and those were the microorganisms
00:14:14.16	inside of his own mouth.
00:14:17.07	So, then we fast-forward
00:14:19.29	to the electron microscope,
00:14:21.27	and the electron microscope
00:14:23.21	was invented several hundred years later,
00:14:25.21	in the late 1960s,
00:14:27.28	and the invention of the electron microscope
00:14:31.02	allowed us to see much more detail in microorganisms.
00:14:34.17	And this was actually the microscope
00:14:37.10	that allowed Lynn Margolis,
00:14:39.22	who I spoke about earlier,
00:14:41.06	to visualize the complexity of the eukaryotic cell
00:14:44.04	and to resolve the fact that,
00:14:46.12	in fact, the eukaryotic cell
00:14:49.07	was the result of a symbiotic association
00:14:51.22	between microorganisms,
00:14:54.22	or among microorganisms.
00:14:57.02	So, then fast-forward a little bit more...
00:14:59.14	although...
00:15:01.22	so, these two characters,
00:15:04.26	Carl Woese and Norm Pace.
00:15:06.27	So, Carl and Norm were doing molecular biology
00:15:10.05	of microorganisms
00:15:11.20	at the University of Illinois...
00:15:13.22	well, Carl was at the University of Illinois
00:15:15.15	and he working with Norm Pace,
00:15:17.08	and they introduced the use of gene sequences
00:15:20.01	to determine relationships in the biological world.
00:15:22.08	So, notice that this is 1977,
00:15:25.04	so it's around the same sort of time that people
00:15:27.25	are beginning to think about using the microscope,
00:15:29.20	the electron microscope,
00:15:31.11	as a mechanism by which to classify the biological world,
00:15:34.26	but this was a new instrument
00:15:36.22	that Carl Woese and Norm Pace
00:15:38.24	introduced to the community of biologists.
00:15:42.08	So, the instrument was the 16S ribosomal RNA gene.
00:15:46.02	It's a highly conserved marker gene,
00:15:48.19	and the reason why this gene could be used
00:15:50.17	was because it's conserved throughout evolutionary history
00:15:53.12	and so it gives you an idea of
00:15:56.24	changes that are very, very old,
00:15:58.12	and would allow you to
00:16:00.21	classify all of the biosphere by molecular methods.
00:16:04.22	And this is the phylogenetic tree
00:16:07.26	that came as a result of the analysis
00:16:10.14	of the biological world.
00:16:12.07	And so what you'll see is you'll see that
00:16:16.15	there are the bacteria...
00:16:17.25	there are three domains of life
00:16:19.09	-- the bacteria, the archaea, and the eukaryea --
00:16:21.26	and the eukaryea contain
00:16:25.12	the animals, plants, and fungi.
00:16:27.09	And so, look at... the animals, plants, and fungi
00:16:30.12	are just these three twigs
00:16:32.03	at the very top of the tree of eukaryea,
00:16:35.21	which is, you know, is showing us that
00:16:39.02	the vast diversity of the biological world
00:16:41.13	is invested in the archaea and the bacteria.
00:16:44.27	So this was a huge change in our world view.
00:16:49.03	So, how big was this change?
00:16:51.20	Well, let's go all the way back to Aristotle.
00:16:56.07	So, Aristotle was one of the first people
00:16:58.08	to classify the biological world,
00:16:59.28	and what Aristotle did was
00:17:01.25	he classified it based on what he could see.
00:17:04.01	So it's animals and plants, basically.
00:17:08.18	So then, you know, fast-forward, as I mentioned,
00:17:11.09	to Anton van Leeuwenhoek,
00:17:13.03	who saw animals, plants, and what he called animalcules.
00:17:16.15	And then, in the 1970s,
00:17:20.20	there was a worker named...
00:17:24.24	who used the electron microscope,
00:17:26.14	his name was Thomas Whittaker,
00:17:27.23	and he developed something called the five kingdom model,
00:17:30.07	and so the five kingdom model
00:17:32.15	had sort of the featureless bacteria and archaea,
00:17:34.22	down here at the base,
00:17:36.11	the protists above that,
00:17:38.07	and those are the eukaryotic cells,
00:17:40.07	and then up at the top he had
00:17:42.24	the fungi, animals, and plants.
00:17:47.20	So, Carl Woese and Pace,
00:17:50.07	looking at this in context with their sequencing,
00:17:54.10	what they had was these three domains.
00:17:57.23	And remember that all, all of this,
00:18:02.05	up here at the top,
00:18:03.24	all of this stuff up here at the top
00:18:05.13	is now invested in this group here.
00:18:09.23	So, it's a huge change
00:18:11.23	in the way we see the biological world.
00:18:13.17	So, what have we done?
00:18:15.12	We have moved from having visual analysis...
00:18:19.02	for a couple thousand years,
00:18:21.22	we looked at the biological world
00:18:23.20	and we classified it based on what we could see,
00:18:27.00	and now what Carl Woese and Norm Pace did
00:18:30.27	was they gave us molecular analysis.
00:18:34.26	And molecular analysis is the... are the genes,
00:18:37.15	and that allowed us to very correctly
00:18:40.12	organize the biological world
00:18:43.23	as it actually exists.
00:18:45.23	So, what we found, of course,
00:18:47.06	is that the biological world
00:18:50.09	is mainly microbial,
00:18:52.11	and the animals, plants, and fungi
00:18:54.02	are but a small patina
00:18:57.07	on the top of the microbial world.
00:18:59.21	So, what did this revolution mean for symbiosis?
00:19:04.21	So, what it meant was that we could identify microbes
00:19:10.09	and determine their relationships,
00:19:12.21	among them and between them,
00:19:14.06	even those that we not culturable.
00:19:15.15	We could extract the DNA from them and say,
00:19:18.04	what is the DNA telling us about who they are and what they are doing?
00:19:21.13	But at first, with Carl Woese in the very, very beginning,
00:19:25.14	sequencing was excruciatingly slow and expensive.
00:19:29.20	And then, around 2006,
00:19:32.10	something called next-generation sequencing
00:19:35.05	came onto the scene,
00:19:36.21	and this has been
00:19:38.22	the most important thing of the whole revolution.
00:19:42.21	And imagine... this was only 10 years ago.
00:19:45.19	So, what happened at this point
00:19:47.29	was that there was a technology-enabled transformation
00:19:51.24	in our ability to sequence quickly and cheaply.
00:19:55.01	So, what I'm showing in this graph
00:19:57.05	is I'm showing the cost of sequencing per megabase...
00:20:02.18	so, you see, in 2001,
00:20:04.14	it was up at about 6000 dollars a megabase,
00:20:07.23	and it followed Moore's Law
00:20:10.03	-- the doubling in computer power every two years --
00:20:15.09	it followed Moore's Law for...
00:20:17.05	until about 2006, down here...
00:20:19.16	until about 2006,
00:20:21.25	and then next-gen sequencing was invented.
00:20:25.25	And look at what happened.
00:20:28.01	It went down from...
00:20:30.01	the cost went down from 600 dollars a megabase
00:20:32.06	to 35 cents in less than 10 years,
00:20:35.19	and now it's down to 3.5 cents.
00:20:38.13	And so this was incredibly enabling
00:20:41.05	to the community of biologists.
00:20:43.05	In other words, lots and lots and lots of people
00:20:45.23	had the resources
00:20:47.17	to be able to characterize the microbial world,
00:20:49.25	and so people have gone all around the world
00:20:53.18	characterizing the microbial world.
00:20:56.10	So, a whole frontier opens...
00:20:58.05	a whole frontier.
00:21:00.10	We can learn, who are the microbial partners
00:21:02.25	of animals and plants?
00:21:04.28	What are they doing?
00:21:06.11	How are they doing it?
00:21:07.18	And what is there importance to health and disease?
00:21:10.18	And so when you're thinking about a symbiosis
00:21:12.28	you think that many...
00:21:15.07	most of them are established new each generation.
00:21:17.19	Not all kinds are,
00:21:19.17	some of them the symbionts are passed
00:21:21.17	in or on the egg,
00:21:22.25	but most of them are established anew each generation,
00:21:25.14	just after birth.
00:21:27.02	And so when a baby is born,
00:21:28.27	what happens is at soon as
00:21:32.01	it goes through the mother's birth canal
00:21:34.12	it begins to acquire its microorganisms.
00:21:36.17	Then there's a development,
00:21:38.08	a trajectory that's not unlike
00:21:41.10	what goes on in the maturation of a forest
00:21:43.22	-- there's a succession of organisms --
00:21:46.05	and in humans you get
00:21:49.09	a mature set of microorganisms
00:21:51.01	somewhere between the ages of two and four.
00:21:53.26	And then what happens is you become a stable association,
00:21:55.29	that changes some over life
00:21:59.22	with various changes and aging and so on,
00:22:02.22	but it's a fairly stable population.
00:22:06.19	So there's a trajectory
00:22:08.00	and we're learning a great deal
00:22:10.16	about how all of this works at this point,
00:22:14.04	but it's new data...
00:22:15.23	I mean, it's just the beginning of the field.
00:22:18.01	What have we learned so far?
00:22:19.28	What we have learned so far is that
00:22:23.01	for many, many, many animals, including humans,
00:22:25.26	the complexity is absolutely daunting.
00:22:28.22	And what do I mean by that?
00:22:30.17	So, let's take humans for example.
00:22:32.12	So, what I'm showing here is I'm showing
00:22:34.11	my favorite comedian, Woody Allen,
00:22:36.09	and I've been very generous with him
00:22:39.25	-- I'm making him 6 feet tall
00:22:42.05	or a little bit over --
00:22:44.03	and so... but his,
00:22:46.14	if you compare the ratio is his size to a microbe's size,
00:22:48.26	2 meters to 2 microns,
00:22:50.22	so he's a lot bigger than a microorganism.
00:22:53.24	However, if you look at the number of genes
00:22:57.21	that Woody Allen has
00:23:00.19	compared to the number of genes that the microbes
00:23:02.18	associated with his body have,
00:23:04.05	the ratio is about 1:1.
00:23:07.18	If you look at cell number,
00:23:09.11	it's thought to be somewhere between 1:1 and 1:10.
00:23:13.11	In other words, there are about 10 times as many
00:23:15.29	microbes associated with you,
00:23:17.12	and that number has just this last year
00:23:20.11	become a little bit controversial,
00:23:21.24	so it's somewhere between here and here,
00:23:24.00	but that is to say that there are
00:23:26.25	just as many microbes associated with you
00:23:28.12	as you have human cells.
00:23:30.01	Then, if you look at gene diversity,
00:23:32.25	because instead of just...
00:23:34.09	so, you know, all of your eukaryotic...
00:23:36.14	all the human cells are of a single genome,
00:23:39.04	but the microbial cells are of
00:23:42.01	thousands, or hundreds if not thousands, of genomes.
00:23:46.07	The difference in gene diversity is thought...
00:23:48.22	for every single human gene
00:23:50.09	there are 200 genes of microbes,
00:23:53.11	so the gene diversity of microorganisms
00:23:55.09	is very much greater.
00:23:57.18	So at this point Woody Allen
00:23:59.22	feels pretty insignificant.
00:24:01.28	What I'm showing here is I'm showing the power of animal model systems
00:24:04.06	for the study of complex characters,
00:24:06.01	and the example that I'm using
00:24:08.07	is developmental biology.
00:24:09.23	And in development biology,
00:24:11.18	what I'm showing here is I'm showing
00:24:13.11	a fertilized egg,
00:24:15.22	and that fertilized egg goes from 1 cell to 10^13 cells
00:24:18.23	and produces something like
00:24:21.02	the miracle of George Clooney, my favorite actor.
00:24:23.14	So, this has been, this has been...
00:24:28.13	this approach has been extremely successful
00:24:30.18	to understand developmental biology.
00:24:34.10	So, what we've been able to do
00:24:36.29	is to take model systems,
00:24:38.15	you know, experiments that evolution has done,
00:24:40.14	and ask how, in this simple model system,
00:24:43.14	a particular developmental phenomenon
00:24:47.11	has been solved.
00:24:49.09	And so what I'm showing is
00:24:51.16	I'm showing an array of model systems
00:24:53.12	and I'm showing ones in which
00:24:55.27	Nobel Prizes have been awarded,
00:24:57.16	and it turns out that 6 Nobel Prizes
00:24:59.28	in developmental biology
00:25:01.14	have been awarded since 1995 and 2007,
00:25:04.06	and all 6 of them went to
00:25:07.24	individuals working on models.
00:25:09.09	So models have been an extremely valuable way
00:25:12.28	to study very complex characters.
00:25:15.09	So, because symbiosis
00:25:17.23	is such a complex character,
00:25:19.18	we feel, those of us in the field
00:25:22.03	who study models,
00:25:23.27	feel that it's a really good way to try to understand symbiotic associations.
00:25:28.10	So, we are developing,
00:25:30.02	the field is developing some models for symbiosis,
00:25:32.17	we're exploiting nature's toolkit
00:25:34.18	and, as I said,
00:25:36.22	evolution has done some enlightening experiments.
00:25:39.17	So what I'm showing here is I'm showing
00:25:41.27	a variety of them,
00:25:43.06	and so there are
00:25:45.05	various nematode symbioses
00:25:47.01	and various other invertebrate symbioses,
00:25:51.19	and we even have, over at UC Berkeley,
00:25:54.19	Nicole King studying the choanoflagellate symbioses,
00:25:58.13	at the base...
00:26:00.05	thought to be the base of the animal kingdom.
00:26:02.26	And then up here some vertebrate models.
00:26:06.05	Now, the vertebrates,
00:26:07.24	all the vertebrates have complex associations,
00:26:09.29	they have large consortia associated with them,
00:26:13.10	and so these people studying over here
00:26:15.10	are really interested in studying germ-free animals,
00:26:18.17	and so I sort of look at them as
00:26:20.21	engineered models.
00:26:22.10	Over here, many of them are studying
00:26:24.19	natural models
00:26:26.16	and these, the invertebrates are
00:26:28.21	naturally very simple associations,
00:26:33.01	and so they lend themselves to looking at a natural situation
00:26:35.12	and how that...
00:26:37.12	how the bacterium and the host animal get together
00:26:40.22	and maintain a stable association.
00:26:43.22	So, I...
00:26:46.17	my lab works on this beautiful animal, here,
00:26:48.24	the bob tail squid.
00:26:51.14	This is not a giant's hand, this is my technician's hand.
00:26:54.08	A very small squid that's indigenous
00:26:56.21	to the Hawaiian archipelago,
00:26:58.25	and this is the symbiosis that I've been working on
00:27:02.10	and that I would like to tell you about
00:27:04.10	in my next lecture.
00:27:07.02	Thank you very much.