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NSF Audio Documentary: The Rules of Life

August 8, 2017

This is a transcript. Find the audio presentation of the Rules of Life at this link.

From the National Science Foundation, this is The Rules of Life.


(dramatic music)

ANNOUNCER: Every year, in January, a small village gets worldwide attention. The world's greatest grandmasters get together with thousands of amateurs to play the ultimate game of minds.


ANNOUNCER: So, you're sitting there and you're watching a game of chess. But you've got a little problem. OK, a big one. You never bothered to learn the rules. Or maybe you only understand one rule: Like maybe all you know is that, except for the king, pieces can't jump over other pieces. But you don't know anything else.


PLAY-BY-PLAY ANNOUNCER 1: F6 is too ugly for contemplation so we have to take and now, knight C -- rook g8 that -- no. Rook g8 hangs the e6.

PLAY-BY-PLAY ANNOUNCER 2: Yeah, but . . .

PLAY-BY-PLAY ANNOUNCER 1: We're not happy about that.


ANNOUNCER: So, there you are and that's the only rule of chess that you know. How on Earth would you possibly be able to predict what a player's next move will be?


PLAY-BY-PLAY ANNOUNCER 2: Maybe you wanna do that. Rook g8, Bishop takes e6 and rook g7 and just say . . .

PLAY-BY-PLAY ANNOUNCER 1: If that's the defense that the world champion to has to rely upon, guess what? I don't like his game at all.


ANNOUNCER: Now imagine, instead of watching a game of chess, you are observing the game . . . of life.


TONY GOLDBERG: Hanging out upside-down under this particular leaf is a little mosquito and that's Culex pipiens.

GRAD STUDENT: This is E. coli genomic DNA. So, it contains all the genomic information for bacteria E. coli strain DH10B.

BEASLEY: Looking down at the ground here, I immediately see a mound of dirt that kind of clued me in that we might be getting close to some ants.


ANNOUNCER: In other words, what if you are a scientist, trying to understand exactly how life on Earth works.

ROBB DUNN: There are more individual bacteria in your gut than there are trees in the rainforests

KRISTALA PRATHER: We have Streptomyces coelicolor; we haveClostridium butyricum; we haveLactococcus lactis.

DEANNA BEASLEY: I'm just going to poke a little hole here and, yep, here we have some fire ants


ANNOUNCER: It's almost exactly like knowing only one rule of chess. Science knows a lot about DNA -- what it is, what is does. But despite all our scientific advances, today we still don't know still don't know some of the most basic rules of how the genes within DNA function.

CARROLL: What kinds of things in their DNA determine that a dog is a dog or that a wolfhound is a wolfhound? That's what we've been after.

ANNOUNCER: Doctor Sean Carroll is a professor of molecular biology and genetics at the University of Wisconsin, and author of the book "The Serengeti Rules."

CARROLL: We can stare at the DNA sequence of a creature, running on for hundreds and millions of letters. Now, that does contain the information for making that creature, but at this level, the genetic information is similar enough between, say, something like a sea urchin and a frog or a human and even a fish that you wouldn't be able to just at first glance look at that DNA and say, "Oh, that is gonna make a human."

ANNOUNCER: And even if science had answered that question -- and remember, it hasn't -- we still don't know how those genes behave out in the world. And so just like with chess,


PLAY-BY-PLAY ANNOUNCER 2: Maybe you wanna do that. Rook g8, Bishop takes e6 and rook g7 and just say


ANNOUNCER: How can you begin to predict with any certainty what life's "next move" will be?

JENNIFER ROSS: That is where we are right now with biology, is trying to understand the rules of life. What are the fundamental principles behind how life not only emerged, but how it's functioning now?

ANNOUNCER: The rules of life -- that rule book that governs every aspect of every living thing on Earth -- every plant, every animal, every disease, every person. From the molecular scale. . .to the entirety of Earth's ecosystems.

CARROLL: Just the pursuit of rules -- thinking that you are not gonna be satisfied until you can sort of constrain the possibilities and winnow things down to a few repeating patterns and make predictions -- that's a very important mindset to have. It's not ubiquitous in science. It's not ubiquitous in biology. Not everybody necessarily thinks that way.

ANNOUNCER: Not everyone. But plenty of biologists -- and other scientists who work in biology -- they do think this way. Dr. Kat Shea is a professor of Biology at Penn State University.

SHEA: When people come to biology, there's a huge amount of variation and a lot of people will look at it and almost throw their hands up and say, "Everything is different and cannot be described according to rules that are used to describe anything else." But I fundamentally believe that that's not true and half the fun is finding out what it actually depends on.

ANNOUNCER: It's half the fun, because -- just like with chess -- if you know the rules, you may be able to figure out life's next move. And that's going to come in pretty handy when you're doing the things biologists do. Things like confidently predicting the future. Dr. Rob Dunn is an Ecologist at North Carolina State University.

DUNN: If the area between Charlotte, North Carolina and Atlanta becomes one giant city, "Charlanta," and it stays that way for 200 years, what can we predict about the ecological and evolutionary trajectories of the species that live there?

ANNOUNCER: Or even tracking a killer.

GOLDBERG: We're in a cemetery and in places like the west suburbs of Chicago. When West Nile virus came into Chicago, we were really not sure why the West Chicago suburbs were a hotspot.

ANNOUNCER: Now, the Rules of Life aren't a total black box. There are a few rules that have been nailed down. At least we think so.

GOLDBERG: The rules of competitive exclusion and competition and evolution.

PRATHER: DNA is going to be transcribed into RNA, and RNA is going to be translated into protein.

CARROLL: Is there an entirely genetic recipe for every different kind of animal, or are there really common ingredients that are just used in different ways? And the answer is the latter.

ANNOUNCER: Largely though, right now we don't know the rules. But imagine if we did: Think of a world where we can predict -- with confidence -- how crops will grow in extreme temperatures, or when cells will turn malignant. By identifying the basic rules of life across scales of time, space, and complexity, we may come to predict how cells, brains, bodies, and biomes will respond to changes around them; how a disease might act in the future; how a disease will respond to a drug, or precisely how much food the nation's farms would turn out next year.


DUNN: Are there central laws -- as we think about the bodies of organisms -- that govern what they would do and that might allow me to predict what happens in some ecosystem I've never seen before?

SHEA: We're looking for general rules that will allow us to address novel outbreaks or novel invasions or novel extinctions so that we don't always have to start from scratch.

CARROLL: All sorts of biologists have been trying to figure out what those rules are. What are the important ingredients that make things the way they are?


SHEA: A fascinating question is, when we look at a community of plants and insects that occur in a native range, and thinking about disturbances -- fires, floods, hurricanes and how very different disturbances are actually fundamentally the same.

GOLDBERG: If it's a directly transmitted pathogen it might follow one set of rules, if it's a vector-borne disease it might follow another set of rules,

DUNN: We're building on the insights from the big general rules to paint a picture of the things we have the most certainty about in what's going to happen in these scenarios. And then to identify the things that are always going to be a little bit muddy.


ANNOUNCER: But the trouble is: Nature seems to do everything it can to make sure humans can't figure out what the rules of life are. In a lot of ways, this makes biology a much more difficult branch of science than others -- like engineering or physics. Ask physicists and engineers. They'll tell you so themselves.

ROSS: We're currently standing in my laboratory which is actually located in the physics department.

ANNOUNCER: Dr. Jennifer Ross is a physicist at U-Mass, Amherst. Her specialty is a critical part of the insides of cells, these tiny things called "microtubules."

ROSS: They're used for the highway system of the cell, and they're also used as the bones of the cell.

She says physics has been about rules from its very beginnings.

ROSS: With Newton and Galileo. And they were just tracking how things fell or how stars went across the sky.

ANNOUNCER: But Jenny Ross is a biophysicist. She works with cells . . .. which are living things. They change all the time. And because they change . . ..

ROSS: A lot of these rules are much more difficult to understand than the simple rules of how an apple falls from a tree, or how celestial bodies go across the sky,


PRATHER: We're now in what's called Building E17 and E18 in the Chemical Engineering Department at MIT in Cambridge, Massachusetts


ANNOUNCER: This is Dr. Kris Jones Prather. What her lab does is invent products that can replace petroleum in things like plastics and jet fuel. She's an engineer -- someone who designs and builds things -- like an engine or a bookcase. But Kris is a bio-engineer who builds things out of living organisms. The tough part there is: you can design a bookcase . . .

PRATHER: And be reasonably confident that the bookcase is not going to spontaneously differentiate into something else.

ANNOUNCER: But a piece of DNA is not a bookcase. It can mutate. It can change. In biology, you're forced to deal with principles like "Diversity," where you have a limited set of rules, but a whole lot of different potential outcomes. You have things like "Emergence," where thousands of individual ants or individual molecules behave individually, but also combine to create some larger system property. Plus, DNA is inside every living thing.


TONY GOLDBERG: American robins, house sparrows, catbirds,

PRATHER: We have Candida albicans, which is a yeast, we've got -- here's a fun one --Archaeoglobus fulgidus.

LAURA RUSSO: We are standing next to carduus acanthoides; it's also known as the plumeless thistle.


ANNOUNCER: There are leaves that are nearly always specific shapes . . .. Animals that are nearly always the same color or size. All of them are that way because of a complex interaction between DNA and the environment. And the nature of this interaction remains almost completely hidden to scientists.

PRATHER: This comes back to the idea that we don't know all the rules.

ANNOUNCER: Every living thing on Earth -- from birds to bacteria . . .. All of them interact with the environment on the genetic level. And what happens is: They interact with the environment. . .which causes changes at their genetic level. . . which in turn changes how they interact with the environment. . .which causes more changes at their genetic level. And on and on and on. Here's Tony Goldberg from the University of Wisconsin.

GOLDBERG: I don't think the fact that we can generate millions upon millions of As, Cs, Gs, and Ts is ever going to let us predict what an organism is going to do in a complex world with absolute perfection. There is a big range of possibilities for what an organism can do in an environment, but more than that, if we think about what our genes are, they're not hard and fast decision-making machines.

ANNOUNCER: No. Genes evolved in an uncertain world and so they're prepared to be flexible, depending on the situation they find themselves in. The biggest gap in biological knowledge -- and this is universally recognized -- the biggest gap is our inability to look at the genetics and environment of an organism and predict the impact they'll have on its observable characteristics. So if you see spikey leaves, or green lizards? There are any number of factors that cause them to be spikey or green, and predicting what those are is extremely complex. By the way, scientists have a word for that spikeiness or that greenness -- those observable characteristics. The word they use is phenotype.


JENNY ROSS: Phenotype

GOLDBERG: The phenotype of an organism.

LAURA RUSSO: Phenotype.

ANNOUNCER: Phenotype is the distinctive set of traits that make something "the way it is." Like if maybe that "something" is biologist Sean Carroll.

CARROLL: Here's this Irish Catholic guy with blue eyes and a graying beard and a little bit of a stomach. You know, that's part of my phenotype -- some of that was hard genetics, the blue eyes. The gut definitely is an environmental influence. We want to understand that interplay between genetics and environment that determines the way creatures are or the way some particular human characteristic is.

ANNOUNCER: The scientific search for this elusive ability to predict an organism's phenotype from what we know about its genetics and environment could help in the lab and in practice -- to address diseases or increase the food supply. And understanding the rules is particularly important if you're looking to manipulate them to make life better.

PRATHER: We can take something like sugar and make biofuels. We could also take the molecules that we can make from things like sugar and make pharmaceuticals.

ROSS: We put in the DNA and we engineer it to make the proteins that we want.


ANNOUNCER: We don't know all the rules that lead from beginning to end, but we have hints to what those rules are. Finding those rules is the essence of what biology is doing in the 21st century. You're listening to The Rules of Life, from the National Science Foundation. Coming up, tracking a killer, cracking the cancer code and looking at Alzheimer's from the inside out. Stay with us.

ANNOUNCER: The Rules of Life, from the National Science Foundation.

(Bird call)

ANNOUNCER: You're hearing the call of a drab, little gray bird that lives along streams in western North America. It's called the Western Wood-Pewee. Now there's another bird that looks almost exactly like the Western Wood-Pewee. And it doesn't just look like it. Scientists use to consider it the same species. It's called the Eastern Wood-Pewee. Here's the thing though: Instead of sounding like this

(Bird call)

ANNOUNCER: It sounds like this.

(Bird call)

ANNOUNCER: Looks like the same bird. Totally different call. You'll find countless examples of this in nature -- in plants and animals. It's evidence of a principle known as "diversity," which, in the scientific context means this: Although a system is controlled by a tight set of rules, the number of outcomes that come out of those rules is almost endless.

CARROLL: In a tropical forest, we understand something about how things interact, but the number of interactions is exponentially mind-boggling.

ANNOUNCER: That's Sean Carroll, author of the book "The Serengeti Rules." Everything from elephants to fruit flies -- worms to octopi -- you can't hope to wrap your head around that kind of diversity in size, shape, color, body parts. . . But even with all that, there is a limited set of rules.

CARROLL: Beneath those incredibly different looking creatures are some basically common ingredients that are used in some understandably variable ways if you can kinda parse all that apart.

ANNOUNCER: One set of rules, huge number of outcomes. The quest for biologists is to cut through the complexity of the outcomes and get a clearer picture of what the rules are. ... Why the Eastern and Western Wood-Pewee sound completely different -- How the genes of plants and animals interact with their environments to create their observable characteristics or phenotypes. Cracking that code holds keys to huge questions like: What causes Alzheimer's Disease, or what causes cancers to form.

ROSS: Cancer is definitely a result of kind of failure modes where you really have a loss of control, and that fidelity that you're supposed to have in your cells.

ANNOUNCER: Parsing out the impact genetics and the environment have on phenotype may help unravel and prevent deadly disease outbreaks

GOLDBERG: If we understand general rules of virus ecology and evolution, we won't be stuck in this endless loop of whack-a-mole -- of trying to respond to each and every new virus that emerges, over and over again trying to invent the new vaccine.

ANNOUNCER: Or make sure farmers have enough bees to pollinate their crops.

SHEA: I can get seeds from the same mother and grow those seeds in very different conditions in the same field and get the plants to be teeny tiny when they flower or three meters tall where I have to stand on a stepladder to measure their height.


CARROLL: Inside a cell is a society of molecules, some of them interacting with others. Inside an organ is a society of cells, some interacting with others. Inside a body is a society of organs, some interacting with others. So, to understand how that whole body works, we need to understand those interactions at each of those scales.

ANNOUNCER: This principle of diversity is one key piece of the puzzle.


ROSS: We have three microscopes in this room that are separated by curtains. And what's in this room over here is our first microscope. It's kind of my baby. It's the Total Internal Reflection Fluorescence Microscope.

ANNOUNCER: Dr. Jennifer Ross at U-Mass Amherst, uses that microscope -- one of the most powerful in the world -- to explore these interactions every day. Sean Carroll talked about understanding the interactions of these societies at every scale. It's tough to get to a scale any smaller than this.

ROSS: When we're watching life at the molecular scale, what we can see that's different is how the players all interact with each other one at a time and this is what gets coupled together over thousands and thousands of molecules inside your body.

ANNOUNCER: This ability to peer deep inside and see the workings of the cell, has upended our understanding of the mechanisms that control existence. Showing that the Rules of Life may be even more complex and harder to understand than we thought. One set of rules, lots of outcomes. For instance: you may remember your science teacher comparing the inside of a cell to a city.

ROSS: And the problem is is that's not really right. It'd be like if you were in a city, but each air particle was really big and it had a big impact when it hit you.

ANNOUNCER: And not just the air. The water hits you too. And the electricity. All the time.

ROSS: It's more like living in a ball pit from, like, Chuck E. Cheese


ROSS: Each one of these balls is actually quite a large object, and it's hitting you, and you're trying to go about your day, but you're being impacted by these things. And maybe some of the balls are sticking to you and changing how you act and, you know, changing where your arm is located. And so that is really hard for us to grasp because we don't live in an environment like that.

ANNOUNCER: That moving and bumping -- that all influences the phenotype for everything on Earth . . .. Why is that leaf spikey? Why is that lizard green? Knowing how the cell works on the microscopic level helps understand this rule set. At the same time, though it reveals multiple outcomes that make it harder to nail things down. That's the trick, Jenny Ross says,

ROSS: How can you take a small subset of things that are really known and see these new phenomena emerge from them that are kind of maybe even unexpected or unpredicted?


ROSS: What we're looking at is the cellular highways or the bones of your cell.


ANNOUNCER: This remarkable microscope let's Dr. Ross zoom down to look at the smallest parts of some of the smallest things on Earth.

ROSS: We decided to hone in on a particular set of molecules that are located in the cell which are called the cytoskeleton.

ANNOUNCER: The cytoskeleton, as the name suggests, acts like the bones of a cell, giving it shape. Her work focuses, in particular on what are called "Microtubules," which are the stiffest part of the cytoskeleton.

ROSS: They're very, very stiff, just like your bones.

ANNOUNCER: She also studies these tiny, tiny elements called Motor Proteins that run along the Microtubules. And we do mean "run."

ROSS: They really do walk, and you can anthropomorphize them, to think of them as kind of like humans with two little feet

ANNOUNCER: Inside every cell, the motor proteins are the delivery trucks and garbage men -- picking up these tiny bags filled either with nutrients or waste.

ROSS: And the cell stuffs things into them so that they can be transported from one place to the other. It's like the luggage of the cell.

ANNOUNCER: By exploring life at this level -- watching the multitude of outcomes that arise out of certain rules -- Dr. Ross is coming to better understand the causes of some serious diseases. See, when all of this machinery is working, cells -- in your brain or muscles or nerves -- can reach out to shake hands with their neighbors.

ROSS: It's actually constantly regulating itself, making sure it's the right length, it's not too long, it's not too short, it's not broken in the middle, right? It's making the handshake with the next cell.

ANNOUNCER: When it breaks down, the cells can retract. Not touch their neighbors. And you end up with a disease like A-L-S, the thing Steven Hawking has.

ANNOUNCER: Motor proteins, running up and down the microtubules of the cytoskeleton make sure the nutrients get where they need to be and that the garbage gets picked up and taken out.

ROSS: You've got to be constantly rejuvenating it with new proteins getting down there.

ANNOUNCER: And when the cells that can't retract or touch each other are brain cells, you end up with another dreaded disease.

ROSS: In Alzheimer's, what you often see is again a loss of attachment -- that handshake between two different neurons is broken. It's broken in a slightly different way than in ALS.

ANNOUNCER: Alzheimer's seems to happen when there are traffic jams along the cytoskeleton -- caused by proteins sticking to each other. That's a particular problem with two of them -- TAU and beta-amyloid.

ROSS: They like each other more than they like the other things that they normally bind to. And that causes these plaques.

ANNOUNCER: The TAU protein is supposed to stick to the microtubules to keeps them from falling apart. When microtubules fall apart, no cargo gets through. The cells retract.

ROSS: And you literally end up with holes in your brain, where the neurons are no longer touching each other. Another place where you can get failure modes that result in disease is in cancer.


SALAITA (lab): On my right there's a simple optical microscope, a microwave, an ultrasonicator.


ANNOUNCER: We're in Atlanta now at the lab of Dr. Khalid Salaita at Emory University, where they've recently learned some remarkable things about how the principal of diversity applies to cancer cells -- answers that come out of a perplexing question when it comes to cells and phenotype.

SALAITA: Are cells responsible for a phenotype or do cells have a phenotype? This is a hard question to answer and a very good question to ask.

ANNOUNCER: Yet another riddle of diversity. To figure it out, Dr. Salaita has conducted precise measurements of genetically identical cells.

SALAITA: These cells are identical. Yet when we perform measurements on individual cells they have different phenotypes.

ANNOUNCER: They took cells from human bronchial tubes, the ones that squeeze, so you can cough.

SALAITA: If you're asthmatic, this is the reason that breathing becomes difficult.

ANNOUNCER: They measured -- on the cellular level -- the mechanics that make your throat constrict. Turns out there's huge variability.

SALAITA: So the question is why. I mean they share the same genetic code, they've been grown in the same way, they have a similar microenvironment, the neighborhood is very similar. But yet they push and pull in different ways. Why is that?

ANNOUNCER: They all have motor proteins carrying cargo back and forth across their cytoskeletons.

SALAITA: How does chemical fuel in the cell get funneled and driven into this mechanical tug? Why are certain cells funneling that energy in a counterproductive way to apply excessive force, and other cells not?

ANNOUNCER: One rule -- motor proteins move along the cytoskeleton. But one cell causes a cough. One cell causes an asthma attack. Now what's truly amazing is how this principle -- that cells can be identical but have different phenotypes -- applies to cancer. As everyone knows:

SALAITA: The majority of tumors are detected mechanically, as in when you feel a lump.

ANNOUNCER: Well, he's done experiments with identical stem cells -- that's cells that can grow up to be any type of cell at all.

SALAITA: You take the identical stem cells and you grow them on a stiff glass slide or a stiff surface, they will take on a fate that is very similar to a bone cell.

ANNOUNCER: But if you grow the same cell on a mushy surface -- like a gel -- it'll come out soft, like a nerve cell. Again: One rule, but somehow, the cell recognizes where it's growing and the proteins move in a way to make it soft or make it hard. Healthy cell? Tumor cell?

SALAITA: Why is that? Does that aid a cancer cell in terms of invading new territory? Does it aid in terms of metastasis? These are outstanding questions.

ANNOUNCER: And they're questions that don't even touch on the most well-known rules of cell biology: When Cells divide, you need to have the same number of chromosomes on each side. When things go wrong there, Jennifer Ross says:

ROSS: You end up with cells that have too many chromosomes, and they end up being kind of monster cells that kind of, they over grow, they create a colony of bad cells as they keep multiplying and growing and, um, and then you get, in the worst case scenario they start migrating out.

ANNOUNCER: A society of molecules inside a cell, some interacting with others. A society of cells inside an organ, some interacting with others. A society of organs inside a body. As we go up in scale, the rule sets stay much the same, so understanding it can help you cope with something that's different, but similar. Here again is Sean Carroll.

CARROLL: W hether or not a cancer cell leaves the main tumor, spreads through the bloodstream, invades another tissue, takes up residence there, and sorta makes a stand, that's very similar to an ecological question of, well: How does something like a virus spread through the animal kingdom and eventually, you know, reach its targets?

ANNOUNCER: It does it a lot like a cancer, in that viruses change the rules that govern how DNA replicates inside a cell. font-family: "Calibri",sans-serif'>There are biologists who work on what's called the "ecology of disease." Moving from a microscopic scale to one that can encompass an entire county.

CARROLL: T hey can look at the scale of nature and ask, well, how does, for example, an epidemic spread?

ANNOUNCER: The answer is: It spreads a lot like cancer. But instead of moving through a bloodstream, a virus will move on a river, or through the air, or sometimes along pathways where we would never think to look.


GOLDBERG: The mosquitoes that transmit West Nile virus are sometimes called tree hole mosquitoes because their natural habitat are holes in trees


ANNOUNCER: This is Tony Goldberg, who we met earlier. He's an epidemiologist at the University of Wisconsin who leads a team that was responsible for cracking one of the most perplexing medical mysteries in the early years of the 21st century.


WOMAN: We had a Chilean flamingo that died. The next day, a bald eagle that had been in our collection for 26 years, she was our mascot, head tremors. Boom. An hour later, she died.


ANNOUNCER: In 1999, birds at New York's Bronx Zoo started dropping dead and no one knew why. Frighteningly, before long, the disease spread to humans.


ANNOUNCER: Another batch of mosquitos carrying West Nile Virus has been found in the Chicago area. Insects collected in Evanston has tested positive for the disease


ANNOUNCER: Doctors knew it was spread by mosquitos, but beyond that they didn't know much else. Tony Goldberg and his team came on the case about two years after that first Chicago outbreak in 2004.

GOLDBERG: A virus is something that takes over the genes of your cell, it diverts the resources inside your cell to make more of itself for its own benefit.

ANNOUNCER: It's this specific knowledge that Tony Goldberg applies when he walks around, both in African jungles and American suburbs, looking for the causes of killer diseases like Ebola and West Nile. Just like with A-L-S and cancer, disease outbreaks are a function of diversity. A constrained rule set with tons of different outcomes.

GOLDBERG: You need something to get sick, and you need something to cause the sickness, a pathogen, and you need a place for them to meet. But what sparks new disease outbreaks are grand coincidences of time, space, and biology.


GOLDBERG: You wouldn't really think that, "Gee, this looks like a place where you would find a vector-borne disease."


ANNOUNCER: Tony Goldberg is standing in a 1960s era suburb, just like the ones he walked through in 2004. At that time, they knew people were getting sick and they knew birds were dying, and they knew both were being bitten by mosquitos. The challenge was to learn the rule set that birthed this outcome. Their approach was to gather data. Lots of data.

GOLDBERG: Data that are as different as a test for a virus in a mosquito and a census-tracked data set on the proportion of houses in a neighborhood built in the 1960s. Those things might come together into a single model that allows us to predict the behavior of the entire system.

ANNOUNCER: They worked first with meteorologists and geographers to see how much rain fell in the area and, precisely where. Thinking

GOLDBERG: If we understand weather, we can understand human disease.

ANNOUNCER: And while they were able to figure out exactly what combination of rain and temperature increased the infection rate of West Nile virus in mosquitoes.

GOLDBERG: Where our rule sets fell apart, was in the link between mosquitoes and people.

ANNOUNCER: They caught dozens of birds and thousands of mosquitoes. They drew blood from the birds and took DNA from the blood in the abdomens of the mosquitoes, to figure out what they had eaten

ANNOUNCER: It turned out the bugs weren't biting just any random birds. They were only biting robins. Then they made their two most important findings: One genetic, one environmental.

GOLDBERG: Culex pipiens is the mosquito that transmits West Nile Virus in my part of the country, in the upper Midwest.

ANNOUNCER: But just like the Eastern and Western Wood-Pewee -- those two little, identical birds that sound completely different, he knew that not all Culex pipiens mosquitos were the same. There's one that really likes to feed on birds, but another the prefers to bite people.

ANNOUNCER: The bugs that ate birds lived in tree holes. The other one didn't. It liked to live underground. In places like storm drains.

ANNOUNCER: So, they knew robins were really important in spreading the disease to humans, and the clue about storm drains helped them put the whole thing together.


GOLDBERG: Right now, I'm standing in a little patch of grass between the sidewalk and the street.

ANNOUNCER: What they found is: these storm drains were largely filled with dead leaves, floating in water. This was a key insight.

GOLDBERG: We looked at these storm drains and we realized that they're designed in a way to drain the water but to trap the leaves,

ANNOUNCER: Their weather data told them it didn't rain often enough to flush out the storm drains completely, and they knew that there's no place that a Culex pipiens mosquito likes better to breed than in water filled with fermenting, rotting leaves. Anyone who lives in the suburbs knows it's not that unusual to have a storm drain right near a tree with a bird feeder that's right near an unscreened back porch. If you're a newborn mosquito

GOLDBERG: I can see over to the house and -- there's a bird at the birdfeeder. So I can go bite that bird. Maybe -- if that bird has West Nile virus, then I will acquire West Nile virus; then I will sit around for a while and digest that meal, and then maybe I'm still hungry. So I will just fly a very short distance over to the person who's sitting on their porch after work and bite that person.

ANNOUNCER: Suburban Chicago's engineering design had inadvertently created a perfect breeding environment for the mosquitoes that transmit West Nile virus. Diversity -- one set of rules, tons of different outcomes -- in this case had created a classic chain of events.

GOLDBERG: Every disease I've studied, I think that exact rule applies. There are a great many steps that have to happen for a microbe to get from one place to another and there are forces that have to operate on different levels, from the behavior of the host to the climate, to the immune systems of the host to the physical property of the agent and they all have to line up in a very long chain of events that, for a single microbe in a single circumstance, seems extremely unlikely and probably is.

CARROLL: That's a beautiful example of the links and the chains. When you first see some phenomenon, you're gonna come up with the simplest explanation you can.

ANNOUNCER: But by keeping in mind the principal of Diversity, you stay alert to all the possible outcomes that might present themselves.



RUSSO: Right now we're at the Arboretum at Penn State University, we're walking north toward a beautiful ridge of trees.

ANNOUNCER: Laura Russo is a post-doctorate researcher. And, if you like being outdoors, she has kind of a dream job. Dr. Russo spends her time in forests and farmland, studying plants and the insects that crawl on them.

RUSSO: I did a research study in New York where we had sampled apple orchards for six years, and in one orchard we sampled it seventy-nine times over the course of six years

ANNOUNCER: She works in the lab of Biology Professor Kat Shea. This isn't a lab working on science to address cancer or Alzheimer's, but their work is every bit as important to human health. Plus, Dr. Shea's work is really important if you're a farmer, or someone who buys groceries or, let's say you're someone who likes to eat food.

SHEA: What I find fascinating is the search for what's the same about a fire and a flood and an attack by a predator. I might think about stress on a community or an ecosystem but you can see that there are rules about how they're structured, what happens if you change them in this way or in that way, can you control them to do what you need them to do? How often you mow or how often a flood happens, all of those lead to emergent properties that are replicable across very different systems.

ANNOUNCER: Emergent properties. That's another key scientific buzzword here. Emergent properties. Here's a way to think about it: It's the way that a hive of bees. . .


ANNOUNCER: Works exactly like the New York Stock Exchange.


ANNOUNCER: Here's the idea behind "emergence:" It's one individual, doing his or her individual thing but in the company of hundreds or thousands or millions of other individuals, all doing their own thing that ends in a single result. One that's more than the sum of its parts. So, traders acting individually can create stock market falls of 500 points in minutes. From a collection of individual nerve cells in a brain you can get consciousness . . . and Beethoven's symphonies.


ANNOUNCER: And ten thousand weeds can grow in a field and attract 300 bees who then go off and pollinate ten acres of apple trees.

ANNOUNCER: Complex networks. Cascade effects. Coming out of a set of rules, with scientists trying to figure out what those rules are.

SHEA: I have always been fascinated by problem systems. I think to understand a system where something is going extinct or where something is invading, you really need to understand how the world works when it's not being disturbed. But then, what's fascinating about it is that you can use the information to actually address critical issues that face us.

ANNOUNCER: Here's one way she does it.


RUSSO: Let's walk over to the bigger population and then we can wander around in the thistles.

There's one.

ANNOUNCER: A principle area of study for the researchers in Dr. Shea's lab is how communities form around different kinds of plants. In particular,

SHEA: I study invasive thistles and one of the plants I study is called Carduus acanthoides. It's about a meter high, it has thousands of little prickly, purple heads and its prickly leaves and prickly stems.

ANNOUNCER: Ranchers hate this thing. When their cattle try to eat them, it cuts up their tongues. Also, it's an invasive species and it's incredibly hard to get rid of. Here's the thing about this thistle though:

RUSSO: Because they have so many hundreds of florets they produce a lot of nectar and pollen.

ANNOUNCER: So as much as ranchers hate them, they are absolutely adored . . . by bees.

ANNOUNCER: They did an experiment here in the Penn State Arboretum to test the impact of this invasive species on bees and other bugs that pollinate plants.

SHEA: We have found that when we add thistles to patches of native species, we can increase both the number of species and the abundance of individuals in those patches.

RUSSO: When the thistle was present it increased bee abundance by over 300 percent and bee species richness by 35 percent.

SHEA: There are lots of good examples of systems where a species that is classified by some as a pest, would be classified by others as beneficial or even entirely desirable.

ANNOUNCER: Not every invasive species is the same. And not every fire is the same, or every viral infection. But studies like this one provide the same benefit as Tony Goldberg's hunt for viruses -- they show that you don't have to re-invent the wheel. You can learn from experience and, in some ways predict the future.

SHEA: Something unexpected happens and one way to look at it is, you have to start from scratch and learn everything about it as if you've never seen anything before. But when you think about the rules of life, if you can draw on your experience from very different systems but say, "Oh, this is also a disturbance," so I can I think about it in the same way that I thought about a flood even though it's actually something fundamentally, biologically different than anything we've dealt with before.

ANNOUNCER: And speaking of predicting the future

DUNN: What can we really say -- not just about 50 years but 500 years, 200 years, 5,000 years -- these are all relevant -- to our human narrative.

ANNOUNCER: That's North Carolina State University Ecologist Rob Dunn, one of the more unconventional minds in science today.

DUNN: I'm fascinated by the idea that I can go into a salt shaker and nobody's ever studied what's living in a salt shaker.

ANNOUNCER: Robb Dunn is the kind of scientist who'll ask thousands of people to swab the dust in their bedrooms to figure out what lives there, or spend hours sniffing and analyzing people's armpits to figure out what dies there.

DUNN: I think we'll spend the next 50 years figuring out all of the interesting ways that the body is choosing which lineages are going to end up in one part of the body or another.

ANNOUNCER: Today, he has two principal preoccupations. One is predicting the future, based on the existing biological diversity in American cities. The other is reorienting how we think about the enormous world of some of the tiniest things we live with every day.

DUNN: I'm fascinated by the reality that these invisible things can be both wonderful and deadly.


ANNOUNCER: You forgot to cover your sneeze. And cold germs travel on your cough or sneeze, you know. Cold germs can fly eight feet to another child's nose, hands or food.


ANNOUNCER: This is, no doubt how you were raised to think about the microbial life that exists on and inside in our bodies. Just like the plumeless thistle that Kat Shea studies, microbes were an invader that humans needed to kill and control.


DOCTOR SPEAKING: The antibiotics seem likely to become our most important weapons against diseases and it seems quite likely that, in time we may actually be able to control most of the infectious diseases that plague mankind.


ANNOUNCER: But today, led by thinkers like Rob Dunn, American science is taking up the principle of emergence, realizing that killing off individuals can wreck systems that are beneficial to human life. They're moving away from this germ theory of disease and thinking more like this

DUNN: We need to disfavor species that do us harm, but we also need to figure out how to favor species that benefit us.

ANNOUNCER: He's done extensive work on the filtering mechanisms in the human stomach, and reached an important conclusion:

DUNN: We used to think that the stomach was mostly an organ for breaking down protein, but it now looks like it's far more important role is actually killing newly arrived microbes before they can get to your intestines, to prevent pathogens from colonizing you.

ANNOUNCER: As a result, once microbes are killed by an antibiotic, it's much more difficult than we thought to repopulate them.

DUNN: There are a whole series of chronic health problems in developed countries that seem to be related to the loss of species we need rather than the presence of species that do us harm.

ANNOUNCER: As we come to understand the causes of Crohn's Disease, multiple sclerosis, asthma, and other ailments differently, academic scientists, doctors and even hospital administrators are coming around to this ecological theory of disease. Another of Rob's focuses these days is trying to understand how life on Earth will change as cities continue to warm.

DUNN: We can make pretty good predictions that newly-evolving species in those cities will be things that sneak around our filters -- things that can avoid being killed by us. They'll rely on the food subsidies we provide, so our waste.


BEASLEY: I have a hand lens with me and that can give me clues as to what species I'm working with here.


ANNOUNCER: This is Dr. DeAnna Beasley, who was a researcher in Dr. Dunn's lab and now an assistant professor at the University of Tennessee at Chattanooga. The close observation work she began with Rob is helping us understand how ants and the parasites and fungi that they live with are changed by heat. By doing that, she says,

BEASLEY: We can start asking questions about, "Well how can we design healthier cities?

ANNOUNCER: Ants are social, just like humans. That means we all deal with similar challenges.

BEASLEY: High population densities, having to manipulate the environment to meet the needs of your population.

ANNOUNCER: Beasley gathers ants and the dirt around them to explore and find solutions to our common problems.

BEASLEY: There are still so many directions that life can go when the environment presents these challenges. That's why these studies are important because understanding just the myriad of ways that life responds to environmental challenges is what's going to be key to understanding how human populations can meet these challenges.

ANNOUNCER: Another scientist working to unravel the rules behind complex behaviors: Ecosystems with their dynamics and diversity. And what it could all mean for us. You're listening to The Rules of Life, from the National Science Foundation. Coming up: Trying to make oil out of germs. Stay with us.

ANNOUNCER: This is The Rules of Life, from the National Science Foundation.


ANNOUNCER: As we've heard, working to understand the Rules of Life can help us track and fight diseases, make our farm land more productive and, sometimes, predict the future. There's another reason why you need to understand the rules. And as big as those other ones are, this one might be even bigger.

PRATHER: A lot of the work that we do is about getting around the rules of life.

ANNOUNCER: That's Dr. Kristala Jones Prather, a Chemical Engineering professor at MIT. Now when she says "getting around the rules," she doesn't mean breaking them, so much as "bending" the rules of life. Here's Robb Dunn from North Carolina State.

DUNN: How do we manipulate the pieces so as to get how each piece affects each other piece, and if we want to think about something practical: How we manipulate the right piece so as to make this a better system in one or another way?


PRATHER (in the lab): I'll put into E. coli one gene from a yeast organism, Saccharomyces; one gene from a mouse; and one gene from a bacterium called Pseudomonas syringae.


ANNOUNCER: Bending the rules of life is something humans have been doing for centuries. It's where domesticated dogs come from, or abundant corn. But today there are more sophisticated ways for humans to bend nature's rules in order to give society what it needs -- whether it's to fight disease, improve food production or to do something else perhaps just as important.

PRATHER: How do we take knowledge and leverage it to make something that's useful?

ANNOUNCER: As populations grow, the world's resources get more scarce. We only have so much oil. So we only have so much plastic or so much paint. But what if you didn't need oil to make that stuff? What if you could just make stuff out of other stuff? That's what Dr. Prather's lab is trying to do. When she talks about leveraging knowledge to make something useful, she means . . .

PRATHER: Being able to get away from our dependence on fossil fuels to make the materials that make a difference in our everyday lives.

ANNOUNCER: The short description -- the elevator pitch -- for Kris Prather's work is this: You start with a germ -- maybe E-Coli. What if you could take that germ, tweak it, and use it to make plastic bags? Or jet fuel, or any of the thousands of other things we use petroleum for today?

PRATHER: W e're actually interested in having the cell make compounds that it doesn't normally make. What we're trying to do is just have the cell take those same simple inputs but now rearrange those molecules in a different way so that rather than getting more cells we get alcohols or we get aldehydes.

ANNOUNCER: Doing that requires that the lab operate under what scientists call the DNA dogma, one of the very few rules of life that we do know exists for certain.

PRATHER: It's really quite liberating to know that that is a rule that we can count on, that DNA is going to go to RNA, and RNA is going to go to protein.

ANNOUNCER: It's safe to assume you know at least something about DNA -- most likely that it's a huge part of what makes you you. What you're probably less familiar with is how it does that, so it's worth a quick step back to explain. Remember, the DNA dogma is . . .

PRATHER: DNA is going to be transcribed into RNA, and RNA is going to be translated into protein.

ANNOUNCER: Protein is critical everywhere in your body. The fluid in your eyeball has protein. You hair has protein. DNA contains the information that tells a cell how to make protein. And scientists can harness that process -- DNA to RNA to protein -- to help make whatever they want, because as Dr. Jennifer Ross from the University of Massachusetts explains

ROSS: Biology never uses anything for one purpose. It takes a lot of energy to make a certain protein, and it tends to kind of re-use that protein complex, or that, even that little piece of RNA over and over again, and it can actually have more than one use.

PRATHER: The cell doesn't need them, doesn't want them--and simply spits them out into a form where we can collect them and use them as end products.

ANNOUNCER: Drs. Ross and Prather aren't biologists. As we mentioned earlier, one's an engineer, the other's a physicist. In both of these fields, Dr. Prather says, scientists

PRATHER: Start by having an observation of the physical world, then you work to develop mathematical models that help you to describe those observations that you see.

ANNOUNCER: But there are limitations to this approach -- complications. For example, being an engineer who works in biology is different from one who designs missiles or car engines.

PRATHER: Part of what makes that so difficult is the fact that biology has this additional layer of evolution.

ANNOUNCER: And along with evolution comes mutation. Sometimes the thing you're working with will change into something you didn't expect. In fact, according to epidemiologist Tony Goldberg . . .

GOLDBERG: This idea of rapid, chaotic change in a world in flux is a rule of biology.

ANNOUNCER: And it becomes a real problem when -- like Kris and Jenny -- your work is to to take DNA from one organism, take DNA from another organism, put them together in a new organism and try to come out with something uniquely different.


PRATHER: We need to find and assemble together in some cases three enzymes, in some cases 10 enzymes--coming together to now allow you to now have a sequence of chemical reactions, and that allows us to go from something very, very basic like glucose into something that would be as complicated as this molecule 4-methylpentanol.

ANNOUNCER: Another vexing thing about designing and constructing things in biology, Jenny Ross says is that . . .

ROSS: We've discovered almost all the proteins that are out there, but we haven't necessarily discovered all of the things that they interact with.

ANNOUNCER: Given that uncertainty, Kris Prather says you can expect that any one of a number of things can happen.

PRATHER: One is that it can work exactly as I design, and I should say from my own experience that happens the least amount of time.

ANNOUNCER: Another is that it will work as designed for a while and then just stop working that way.

PRATHER: And yet a third thing that could happen is that it can work the way I've designed it, but for reasons that have nothing to do whatsoever to my design.

ROSS: All of these rules that we understand at a particular temperature, they're kind of all thrown out the window as soon as we start adding in balls that can move themselves, or can affect other balls, and that's really what's happening in biology, and that's what we're trying to understand.

ANNOUNCER: And temperature's not the only variable. Change whether you add oxygen, change any number of other inputs. You can end up with any number of outputs.

PRATHER: I may not know which environmental variables or which factors within that context, if they were changed, which one of those changes would actually have some significant impact on the outcome.

ANNOUNCER: No there is no question, messing around with DNA can be dangerous. Scientists and the world learned that lesson eighteen years ago.


GELSINGER: Less than 24 hours after they injected Jesse with the vector in an amount only one other person had ever been given Jesse's entire body began reacting adversely.


ANNOUNCER: In 1999, the death of an 18-year-old college student named Jesse Gelsinger shined a harsh light on gene therapy research. This is Jesse's father, testifying in Congress in 2000.

GELSINGER: As a result of Jesse's death, many important issues regarding gene therapy have come to light. The number and lack of proper reporting of adverse events associated with gene therapy, the secretive nature of gene therapy research and the motivations behind the race for results are what trouble me most.


ANNOUNCER: A lesson many learned from that episode was humility. And caution. Both are important as technology advances. Kris Prather's lab works with a gene editing tool called CRISPR-Cas 9.

PRATHER: What CRISPR or CRISPR/Cas9 is is just a method of making changes to DNA.


GRAD STUDENT: I have a CRISPR knockdown system where it allows me to specifically repress transcription of a gene of interest.

ANNOUNCER: The changes can be made as easily as editing a document in Word. Here, one of Dr. Prather's graduate students is using CRISPR to make sure they end up with less of whatever gene they're targeting.

PRATHER: It's allowed us to make changes in a range of organisms that were previously fairly inaccessible and recalcitrant to being able to make genetic changes. And it's pretty fast.

ANNOUNCER: There are things she loves about this tool.

PRATHER: The beautiful thing about CRISPR and why it has really taken off the way that it has is that it seems to work in every organism that anybody has tried to get it to work in.

ANNOUNCER: But Dr. Prather approaches it with an open mind.

PRATHER: There's not a lot of motivation to publish the things that don't work. If people are trying and trying and trying and failing to get this to work, that's something that usually doesn't appear in the published literature.

ANNOUNCER: But labs like hers and like Jennifer Ross's lab at U-Mass keep at it, because the potential results are just amazing.

PRATHER: How do we push the limits of what biology can give us for chemical manufacturing and really be able to compete on equal footing with pumping oil out of the ground and have that give us the wide range of chemicals and materials that we need for our everyday lives? To make medicines that we couldn't make before, to make fuels that we couldn't make before, and to make chemicals that we couldn't make before.

ANNOUNCER: And in Jenifer Ross's case, we really do move from science to what seems the realm of science fiction.

ROSS: This is a place where biology can really teach us something about how to do this. These emergent phenomena that occur in biology are something we don't know how to engineer right now, and it's really a frontier area of engineering.

ANNOUNCER: Ross studies the operation of cells on the most minute level -- understanding how they operate, what they can sense, how they react.

ROSS: I really want to be able to take a lump of goo, which is programmed in a sense that I know exactly what's in that lump of goo. And I want to be able to put in all the right materials so that that lump of goo can go into a coal mine collapse. And can actually go and find the miners, and then not only find the miners and detect them, but actually rearrange so that they can, it can create an arch that would support the miners being able to escape.

ANNOUNCER: Advances like this -- and others we've discussed -- can only happen once we understand the basics. This is the importance of what's called "basic science." But as Kris Prather says,

PRATHER: Foundational basic science advances have always led to technological achievements but they have also almost always been unpredictable.

ANNOUNCER: As NC State ecologist Rob Dunn says,

DUNN: It's one of these things that forces us as arrogant humans, content in the idea that mostly we understand stuff, to think, "Oh, maybe we don't understand that much stuff."

ANNOUNCER: These are exciting times in biology. . .because we now have the tools to start filling in the gaps -- the unknowns -- to discover and, yes, understand the rules behind the dazzling complexity that is life.

CARROLL: Knowing the players and knowing the rules that govern their play, that's the only chance you have to sort of step into the game and make a good move. Medicine depends upon on that sort of knowledge, agriculture depends upon that sort of knowledge. The management of the planet depends upon that sort of knowledge. Know the players, know the rules, and now you're in command.

ANNOUNCER: Because, as we all know, you'll never get to checkmate if you don't know the rules.


ANNOUNCER: The Rules of Life was written and produced by Richard Paul with help from Cliff Braverman. We would like to thanks James Olds, Brent Miller, Floh Thiels, Caitlin Schrein, Michelle Bushey, Leslie Rissler, Susanne von Bodman, and Jessica Arriens. We had technical help from Andrew Howard, Brady Carlson, Nancy Cohen, David Goodman, Mike Miller, and Eleanor Klibanoff. Original music was composed and arranged by Lenny Williams. This program comes to you from rlpaulproductions and the National Science Foundation. I'm Richard Paul.