Author and journalist Carl Zimmer talks about E. coli, the bacteria that are the subject of his new book Microcosm: E. Coli and the New Science of Life. Web sites mentioned in this episode include www.carlzimmer.com

Podcast Transcription

Steve: Welcome to Science Talk, the weekly podcast of Scientific American for the seven days starting October 8th, 2008, I'm Steve Mirsky. This week on the podcast: Carl Zimmer with everything you ever wanted to know about E. coli, and some things you probably didn't want to know. Plus, we'll test your knowledge about the Nobel Prizes awarded this week. First up Carl Zimmer joins us again. He is the author of the new book Microcosm: E. coli and the New Science of Life about the fascinating bacteria that live in each of us and the fundamental role it's played in the history of modern biology. I recorded a talk that Carl gave last month at Stevens Institute of Technology in Hoboken, New Jersey. After the talk, Carl and I had a brief conversation, but I am going to play that first, because it wound up being a good intro to his talk. This week's episode is longer than usual because I thought you would be interested in everything Carl had to say, so I have broken it into two parts to keep the file size as manageable while maintaining audio quality; and away we go.

Steve: E. coli is obviously fascinating we have, what did you say, we have about a billion of them in our bodies at any one time? But what the zest [possessed] you would [to] actually spend, however many years you spend [spent], churning out—what 100,000 words—on E. coli?

Zimmer: Well I remember if anyone asked me that with some concern and the answer is pretty simple. I have been getting really interested in really basic questions about life, about what it means to be alive. Are there basic rules that all living things have to obey here I [o]n earth or other planets? And what's cool is that scientists are actually starting to address those questions in meaningful ways and they continue to start talking about the rules of life; and at first I thought that would be what I would write a book about, and then I realized that would be a bit crazy because that, it's actually a book of [that] may be several thousand pages long. So I thought, how can I focus it, how can I narrow down to really tell a compelling story? And what occurred to me was that just about holidays, things I have been reading about the scientists who were doing this research—they weren't just studying any random organism, they were all studying E. coli. And the reason they were studying E. coli is because it's the best understood species on earth, and so when they want to ask really deep questions about life, they want to stand on the shoulders of giants. They want to take whatever one has learned about E. coli and then ask an even deeper question using E. coli. So and once you jump in there, into the world of E. coli, it's quite a fascinating place to be.

Steve: Is it in some ways that the simplest organism that has solved—I mean any bacteria, you could possibly ask yourself—but is it the simplest thing that has solved the problem of being alive?

Zimmer: E. coli is actually not very simple; it's tiny, but it has got about 4,000 genes; and, you know, there are other bacteria that just have a few hundred and, you know, viruses may have just a handful of genes.

Steve: And whether they are alive or not is a different question that we will [won't] bother of [with] now, but ...

Zimmer: Yeah. Now that E. coli is very interesting because it is actually highly evolved you can say. It's very well adapted to living inside warm blooded animals that eat a lot of food that gets broken down into sugar. They can break down all sorts of different kinds of sugar; they are [in]credibly versatile. They are equipped to deal with all sorts of nasty circumstances like getting scorched or frozen or so on. They are incredibly versatile. If you went back to the origin of life, you would not find something like E. coli there. E. coli is quite sophisticated in its own way.

Steve: It's no [not] like my intestines are the most easy environment to get along in.

Zimmer: No, it's a jungle in there. I mean …

Steve: It's a jungle in there …

Zimmer: They have to fight with about 1,000 other species of microbes to survive; they are all jostling and competing and cooperating to survive on your food, and, you know, they have been doing it very well for millions of years, but it's not easy in there.

Steve: And what are they doing for me in there? They are helping me digest things?

Zimmer: Yes, they are probably doing a number of things for you. One of the things they probably are doing is making it a nicer place for other bacteria to live that actually produce nutrients that you need. So what they do is they suck up a lot of the oxygen. The keep the oxygen levels very low so that bacteria that can only live in low oxygen can thrive, and it's those that start converting your food into some compounds that you need. So it's a whole ecosystem in there that's serving you, and E. coli is part of that ecosystem.

Steve: They are like a keystone species in that ecosystem.

Zimmer: Yeah, you know if you get rid of your E. coli, it's probably not a good idea because not only are they helping to keep the ecosystem in balance, but they actually help keep out bad bacteria. They make it difficult for bad bacteria—including bad strains of E. coli—to invade your ecosystem.

Steve: In you [your] copious research for this, what really blew you away? There must have been something that you came upon that you just were really surprised by.

Zimmer: I was really blown away when I spent the time to understand some of the networks of genes that E. coli uses to deal with things like overheating or something, where you have got 10 or 20 genes that are fit together, kind of like the components in [a] the circuit. And I would actually talk to engineers who study E. coli and compare it to your own autopilot system, and they would show me just how there are these feedback loops and things that have build [are built] into E. coli that, you know, that are built into your iPod or some other piece of electronics. The same principles are it [at] work, and I just thought that was so cool.

Steve: Because without those you don't get to carry on your functions inside my intestines.

Zimmer: Right, I mean things are changing all the time for E. coli. I mean, it's not like it is living in some Petri dish in fixed conditions. Things are always changing, and [they've] got to be ready for change; and the way to be ready is the [they] have a way to respond and these genetic networks that they have, they let them do that.

Steve: So E. coli are the ultimate boy scouts: "Be prepared".

Zimmer: Indeed, indeed; ready for anything.

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Zimmer: This book came out of a basic, simple question that started really bothering me, which is, simply, what is life? Another way of asking that question is what does it mean to be alive? You know, a human being has something about her that is shared by a mosquito, in [an] elephants, in [an] orchid, but which is not shared by other things in nature, like a hurricane or a rock. What is that thing? Is there in fact a thing that you can use to distinguish life and nonlife? This is a really old question and my downing [dealing] with it is hardly the first time that anybody has wondered about it and; no less than Aristotle wondered what it meant to be alive. And for Aristotle and other Greeks, they thought about life as what they call a psyche or the soul and so that would distinguish living things from nonliving things is that they had this soul, whatever it was. And this soul was, in a sense, the end or the purpose for the thing being alive in the first place, and is the essence in a, sort of, the complete thingness as it were of something that's alive and it's the source or the origin of its movement. So it's what gives it what we might call the energy to move around, to be alive and some 2,000 years later, in the mid 1900s scientists were asking this same question all over again. But a lot of the people who were asking this question were physicists—so, someone like Irwin Schrödinger, who was just coming off of the great triumph of quantum physics. These physicists had made huge strides in understanding that there is underlying nature of matter, of understanding electrons, of atoms, and so on, and being able to understand matter with incredible precision, but then I [they] looked over at life and they scratch their head, because it does not make sense. And, you know, how is it that a living thing can reproduce and give rise to something that's basically just like itself? And at that time, scientists were still trying to determine what genes are, the things that allow one living thing to give rise to another living thing. They don't [didn't] know what genes were, you know, they were tiny, incredibly tiny, and so how was it that that all of the instructions, as it were, for building basically a replica of [a] living thing could be stored in such incredibly small spaces. And so Schrödinger wrote a book actually called What is Life? in 1944 where he wondered aloud whether maybe we need ed a whole new set of laws, maybe life really did defy the rest of the universe. Today, we actually have a pretty good handle on what life is. And it turns out that we got a lot of our insight into what it means to be alive from one species, but it wasn't humans. In fact, if you really want to understand what it means to be alive, humans are a lousy choice. For one thing we are just really complicated. So we have this huge genome, our DNA, if you thought of it as letters, you have about three and one half billion letters long. There are probably about 20,000 genes in there that encode proteins, but those make up a tiny slice of, all of our DNA. The rest is just total wilderness; a lot of it might not do anything or might do things we don't yet understand. So we actually don't understand ourselves very well at all even now. And so if you want to understand very precisely what it means to be alive, stay away from humans. What I talk about in my book is how scientists discovered a lot of what it means to be alive by studying E. coli. And I know this might sound hard to believe if you haven't taken a class, say in molecular biology. If I say E. coli to you, you probably think about tainted spinach; and you probably should, because you don't want to eat spinach that has E. coli in it. It could kill you. You also want to make very sure you cook your hamburger all the way through, because you don't want to get E. coli there. However, there is more to the E. coli than just tainted spinach. E. coli live inside all of us, quite happily, and for scientists E. coli has come to become almost like an icon. It speaks to them about what it means to be alive; this thing that lives inside of all of us. Before I explain a little bit about how this came to be, let me just tell you a little bit about E. coli.

So, each and every one of you carry about a billion or so of them inside of you right now. So we have, you know, maybe 50 billion E. coli in the room I salute you . You were not born with E. coli. You were born sterile, and then your mother, maybe a nurse, slowly began to infect you with maybe about a 1,000 different species of bacteria and other microbes and one of those species was E. coli. E. coli probably got in there very early. It's a kind of a pioneer. So [it] got into your intestines and it started to thrive. It probably fed first on the sugar in the milk that you drink called lactose, and then it shifted to over to other kinds of sugar as your diet change[d] too. And you are going to have this E. coli until you die. We can fit about 10,000 of them across your finger. Each one has about 4,000 genes; if you would add up all the molecules inside of it, proteins and so on, you might get a figure like 60 million. shape [They're shaped] kind of like a rod; maybe you can think of it kind of [like] a submarine. So all living things need to have a sense of where they are, and E. coli is no different. It has thousands of receptors on its front end which grab on the molecules as it's drifting around inside of you—and it doesn't have a brain—and they can take that information and process [it] in a very complicated way to figure out where to go. Obviously it does not have a map, so it has to figure out a pretty simple way of getting around. So what happens is that the information that these receptors pick up gets transferred down to the motor that spins the flagellum. Now the flagellum can only do two things. It can spin clockwise or counter clockwise. It does it hundreds of times a second. If they spin counter clockwise, the flagella all, kind of bundle together and they send the bacteria forward; if it goes the other way clockwise, the flagella fly apart and it just goes into a tumble because the flagella all are spinning in different directions. So that [is] all it does, it goes straight and it tumbles, straight tumbles, about a second usually of swimming straight and then tumbling for a tenth of a second. They might think this is a ridiculous way of getting around. I mean, imagine that you are driving down the road and you [you're] just like, "Okay, and I'm just going to just drive in a straight line, and every second when I close my eyes and just throw the steering wheel and I will just open my eyes when we stop bumping around and then I will just go in whatever direction we were going. Actually, though, this works pretty well for E. coli, because what it can do is it can change the amount of time that it swims in a straight line, so when it picks up some of those molecules I was telling [you] about with its receptors, if these are molecules that might be a sign of, say food, it will swim longer before tumbling. So [it would] be more likely to be heading towards their target. If it tumbles and it ends up heads away, it's not going to be detecting those molecules as much and so it's going to swim in a straight line for a shorter period of time and it's going to tumble more. So that's going to end up bringing it back to its target. So you can actually put E. coli say in a maze and give it some sort of food to go after and they will make their way to it; that's obviously not a straight line but it doesn't need to be a straight line. Straight lines are overweighed [overrated] in nature.

E. coli is totally packed with DNA. If you were to take the DNA inside of E. coli and stretch it out, it would be around [a] thousand times longer than the microbe itself. So obviously this is a very carefully arranged molecule inside this thing. It's coiled up, and it's got little clips hooked onto [it] in different places and the microbe is constantly reading the DNA to make proteins and it is also copying it. The great thing about E. coli for scientists is that it grows really fast. At its fastest, it can divide about once every 20 minutes. If it could keep that rate up after a few days we would be basically swimming through an ocean of E. coli that cover [covered] the world; and in order to do that, it has got to copy its DNA and it does it just about perfectly—about 3,000 letters of DNA every second, generally without a mistake. Every now and then, every few billion letters, it makes a mistake, and that's very important and I will talk about that later. So, as you have this bacteria replicating, copying their DNA, they explode, and then you have lots of bacteria. They run out of food before they can take over the world, but they can then hang in there, they can actually go into a kind of state of suspended animation. You know, for example we all have E. coli inside of us; a lot of it leaves us in a way that I don't need to get into, but in any case E. coli ends up in the soil and in the water and there's not a lot of food out there for it. So they can kind of go into a state of suspended animation; and scientists have found that even after 5 years they can be revived and come back to life. So how was it that this odd little microbe got to be this icon of science? It was discovered in the mid 1880s by a German pediatrician named Theodore Escherich who was trying to figure out why [it] was that all, so many, I should say, of his patient's babies were dying.

In Germany, in the late 1800s, [an] incredible number of children were dying often of diarrhea and Escherich had this radical idea that was called the germ theory of disease—that bacteria of all things can make you sick and very few people really accepted this at that time, but Escherich thought that this was the best way to understand why these children were dying. And he was right; and what he decided to do was to first look at all the bacteria that live in healthy children. So he started collecting diapers and trying to culture bacteria out of the stuff that you find in diapers. And one of the things he found was this fascinating little rod-shaped microbe that grew really fast in his lab where there is a lot of oxygen and which he could feed just about anything. He could feed them on potatoes, on blood, on milk; he was quite fascinated. by it a [And] he called it Bacillus communis coli. And then after his death, it was named in his honor, Escherichia coli, but we call E. coli for short. In the early 1900s, scientists started to use bacteria to run experiments about some of the basic questions about life. So how is it that life takes food and turns it into more life? And E. coli and a lot of other bacteria were good to use. They were safe, they grew fast, they didn't mind being in a lot of oxygen in the lab so you could study them in. for example, a petri dish.

Another nice thing about E. coli is that it gets sick. Now at that time, viruses were even more mysterious than bacteria or genes or what have you. People just had no idea what viruses were. They knew they had proteins in them and they knew they had DNA. They didn't know what the viruses did with it, but some scientists such as Max Delbruck and Salvador Luria started to infect E. coli with its viruses and see what happens. which [What] Scientists were able to do eventually, was to use E. coli and its virus to support the idea that genes are made of DNA. They did a very simple experiment. All they needed was E. coli, viruses and a wiring blunder. They tagged the DNA in the virus with a radioactive tracer and then they let it infect a colony of E. coli and then they spun the bacteria and the virus on the outside apart, ripped them apart and they said, "Okay what is now inside of the bacteria" It turned out it was DNA inside of it. They could see a rare activity from the DNA that could be detected inside the bacteria. When they did the same thing to the proteins they found that the proteins were outside the bacteria. So the viruses were inserting their DNA into E. coli and somehow E. coli was then making viruses. Another big step for E. coli was when scientists discovered that E. coli has sex. It's not the kind of sex that we're accustomed to. What happens is that a microbe will build a long tube and it will stick that tube into another microbe and then pump some DNA into it and then the tube breaks off and the two bacteria goes in [go their] separate ways. Joshua Lederberg who recently passed away discovered this—and like many other people who studied E. coli—got the Nobel Prize for his work and this was a huge help, because you could now transfer genes from one E. coli to another and start to figure out what those genes actually did. So we know now that DNA is the stuff of genes, now lets figure out what those genes do. So for example, if one microbe is resistant to antibiotics and the other one isn't, if we let them have sex, maybe one of them will pass the resistance gene on to the other one and we can figure out where it is by seeing how long it takes for that gene to get from one microbe to the other. Another group of people got the Nobel Prize for studying E. coli by asking another really simple question, which is, if genes are made of DNA, and if genes are responsible for making proteins, then why aren't all genes making all the proteins all at once?

So you know if I have got a cell in my finger, it has got all the genes necessary for making an eye or making bone or making saliva and I am very glad that it's not doing any of that, and I am glad that it is only using the genes that it needs to be a skin cell, so why are genes so obedient? The reason is that there are switches that can turn genes on and off and the first place where scientists discovered these switches was in E. coli. So for example, E. coli like I mentioned, can eat the sugar in milk. To do so it has to make special enzymes to eat that sugar and it only makes those enzymes if it is exposed to that sugar—it's a signal in a sense—and what happens is that a protein falls off of those genes and essentially the genes switch on and start making their enzymes. This kind of set up is basically what you find in humans, just as so many other things about E. coli turned out to be true for humans and all living things. So François Jacob once said famously "What is true for E. coli is true for the elephant." So by the end of the 1960s, E. coli had become this amazing tool for scientists and it had led them answer questions that just 30 years ago previously had been complete mysteries. And so Max Delbrück when he won his Nobel Prize in 1969, he gave a speech where he declared "This riddle of life has been solved." So that [it] has been 40 years since Delbrück said that, and I think it is safe to say that he was a little bit hasty, not to diminish the importance of his work and the work of other people on E. coli, but that's not all there is to being alive. I mean, you can just look at E. coli, and you can see there's a lot more here than just that DNA molecule inside of it. Life is the coordination of all these molecules to keep this thing alive. Today, scientists have been cataloging E. coli's genes and it has about 4,000 genes and you can actually go online and see these giant atlases of its DNA, which is quite amazing. Scientists understand E. coli on the gene level much better than they do humans. Most of the genes in E. coli, scientists understand quite well; but one gene by itself doesn't do anything. One gene by itself does not give E. coli life. Genes have to work together and then it gets back to the switches that I was talking about before. They have genes that switch on other genes, genes that turn off other genes and genes that have to work together, and it is the interaction of those genes that allows them to be alive and to respond to its world. So you can think of it, really kind of, like circuitry; almost like, say, a microprocessor in a computer. So you have diagrams that show you how E. coli deals with heat, for example. So if E. coli gets a little bit hot, it's very dangerous; because it's protein[s] start to unfold, they don't work right, and then it dies. So it has to make proteins that can fold the other proteins back into the proper shape or if they get too tangled there they could just cut them off and destroy them before they can cause real damage.

E. coli can make tens of thousands of these, what are called hitchhike proteins, in a matter of minutes, when things get too hot, and it can just make the right number that it needs. It acts like its got a little thermostat inside of it. So if you cook it at like 100 degrees, it will make a certain number of hitchhike proteins; at 102 degrees it will make more; turn the heat back down, it gets rid of the extra ones. It's able to do this because of this very complicated network of genes switching on other genes, turning off other ones; there are feedback loops built into it. So that [the] more of one protein you build, those proteins come back and destroy the proteins that help made [helped make] them. It's wonderfully complicated and in my book, I talked to an engineer named John Doyle from Caltech who studies the E. coli. Now his background is in things like [the] space shuttle and figuring out how to keep the space shuttle from flying out of control when it is re-entering atmosphere. He sees the lot of the same principles that [at] work in E. coli. So E. coli has its own kind of autopilot system built into it. So that it can go about doing its [these] things and not die if the temperature changes, for example, and that system is built into the way that the genes work together. So you have to understand all the genes together, and scientists don't really have that picture even of E. coli yet. They call it a complete solution of E. coli and they might get it in say 10 years but they don't have it now and certainly they don't have for humans and probably won't have it for a century.

(music)

Steve: That concludes part I of this podcast. We will pick it up right here in part II.

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