NOVA Wonders Can We Make Life?

Transcript

NOVA Wonders Can We Make Life?

PBS Airdate: May 23, 2018

TALITHIA WILLIAMS: WILLIAMS (Mathematician, Harvey Mudd College): What do you wonder about?

ERICH JARVIS (Rockefeller University): The unknown.

FLIP TANEDO (University of California, Riverside): What our place in the universe is?

TALITHIA WILLIAMS: Artificial intelligence.

ROBOT: Hello.

JARED TAGLIALATELA (Kennesaw State University): Look at this. What's this?

KRISTALA JONES PRATHER (Massachusetts Institute of Technology): Animals.

JARED TAGLIALATELA: An egg.

ANDRE FENTON (Neuroscientist, New York University): Your brain.

RANA EL KALIOUBY (Computer Scientist, Affectiva): Life on a faraway planet.

TALITHIA WILLIAMS: NOVA Wonders, investigating the biggest mysteries…

JOHN ASHER JOHNSON (Harvard-Smithsonian Center for Astrophysics): We have no idea what's going on there.

JASON KALIRAI (Space Telescope Science Institute): These planets in the middle, we think are in the habitable zone.

TALITHIA WILLIAMS: …and making incredible discoveries.

CATHERINE HOBAITER (University of St Andrews): Trying to understand their behavior, their life, everything that goes on here.

DAVID COX (Harvard University): Building an artificial intelligence is going to be the crowning achievement of humanity.

TALITHIA WILLIAMS: We are three scientists, exploring the frontiers of human knowledge.

ANDRE FENTON: I'm a neuroscientist, and I study the biology of memory.

RANA EL KALIOUBY: I'm a computer scientist, and I build technology that can read human emotions.

TALITHIA WILLIAMS: And I'm a mathematician, using big data to understand our modern world. And we're tackling the biggest questions…

SCIENTISTS: Dark energy? Dark energy!

TALITHIA WILLIAMS: …of life…

DAVID T. PRIDE (University of Califormia, San Diego): There's all of these microbes, and we just don't know what they are.

TALITHIA WILLIAMS: …and the cosmos.

On this episode…

KRISTALA JONES PRATHER: D.N.A. is really just a chemical.

TALITHIA WILLIAMS: We're rewriting the code of life, like never before.

DREW ENDY (Stanford University): There's enough D.N.A. to make 30 copies of every human genome on the planet.

GEORGE CHURCH (Harvard Medical School): You can change every species to almost anything you want.

TALITHIA WILLIAMS: Can this new genetic power save lives? Or even bring extinct creatures back from the dead?

BETH SHAPIRO (University of California, Santa Cruz): Could we bring a mammoth back to life?

TALITHIA WILLIAMS: It's a revolution in biology.

DANICA CONNORS (Nantucket Meeting Participant): This is rapid, man-made evolution.

TALITHIA WILLIAMS: NOVA Wonders: Can We Make Life?

The earth is brimming with an unimaginable variety of life, a multitude of creatures, connected and intertwined in countless ways.

ANDRE FENTON: They've evolved over a billion years, driven by a very simple code.

RANA EL KALIOUBY: For decades, scientists have been trying to master this chemical cipher that we call D.N.A.

TALITHIA WILLIAMS: Now, suddenly, new tools are allowing researchers to manipulate the code of life with incredible precision. How powerful is this?

RANA EL KALIOUBY: Could we change and mold life at our command?

ANDRE FENTON: Could we bring extinct creatures back from the dead?

TALITHIA WILLIAMS: How much power do we really have over life? And are we ready to use it wisely?

ANDRE FENTON: I'm Andre Fenton.

RANA EL KALIOUBY: I'm Rana el Kaliouby.

TALITHIA WILLIAMS: I'm Talithia Williams, and in this episode, NOVA Wonders: Can We Make Life?

Fifteen-thousand years ago, the biggest thing on four legs was this guy, the mammoth. These eight-ton giants threw their weight around, from the steppes of Europe to the plains of North America, until they vanished from the face of the earth.

BETH SHAPIRO: From the paleontological record, the best guess is that there were many mammoths, potentially hundreds of thousands, even to millions of mammoths.

TALITHIA WILLIAMS: Evolutionary biologist Beth Shapiro deciphers the D.N.A., the genetic code, of ancient animals, like the Ice Age mammoths discovered here, in Hot Springs, South Dakota.

BETH SHAPIRO: It's a absolutely unique site, really amazing. This is a ancient sinkhole, where lots of mammoths would have wandered up into a lake to have a drink, and once they got stuck, would've not been able to get out.

There are about 60 mammoths that are in this site in a pretty tightly- condensed little geographic area.

TALITHIA WILLIAMS: These animals died about, at least 26,000 years ago, before people came to North America. When human hunters did show up, mammoths wouldn't stand a chance.

BETH SHAPIRO: People might have been that proverbial straw that breaks the camel's back. These animals were in trouble because the climate was changing, because there wasn't enough habitat available to them, just not enough to eat. And then just at that really worst moment, people turned up.

TALITHIA WILLIAMS: Pretty soon, all the mammoths, including the iconic woolly mammoth that loved colder climates, would go extinct, gone forever. Or are they?

If George Church has his way, he will bring the woolly mammoth back from the dead, to roam the earth once again. Kind of tall and woolly like a mammoth himself, George is one of the world's most inventive genetic scientists.

He once coded his latest book in D.N.A. and brought it on this piece of paper to the Stephen Colbert show.

GEORGE CHURCH: They took the book, including the photographs…

STEPHEN COLBERT (The Late Show with Stephen Colbert): Yes?

GEORGE CHURCH: …zeroes and ones, converted to A, C, Gs and Ts.

STEPHEN COLBERT: Which is the code of D.N.A? Put a little drop…

GEORGE CHURCH: A little drop right there.

STEPHEN COLBERT: That contains the D.N.A. in there.

GEORGE CHURCH: That's right.

STEPHEN COLBERT: So, this piece of paper, right there, contains 20-million copies of this book?

GEORGE CHURCH: That's right.

STEPHEN COLBERT: Well, Dr. George Church…

TALITHIA WILLIAMS: But can this genetic magician possibly resurrect a long dead woolly mammoth?

GEORGE CHURCH: Every species on the planet comes from a cell with a genome, and that means you can change it to almost anything you want.

TALITHIA WILLIAMS: George is like the fictional scientists from Jurassic Park. They "de-extincted" dinosaurs by implanting their D.N.A. into ostrich eggs.

RICHARD ATTENBOROUGH (As Hammond in Jurassic Park): Come on, little one.

TALITHIA WILLIAMS: The baby dinosaurs that hatched were cute at first, and then they weren't.

Despite the movie's dubious science, George's de-extinction idea is not very different. And, fortunately, his creatures are vegetarians.

George's real life plan is to take mammoth genes, decoded from ancient remains and implant them into the embryo of a live Asian elephant.

GEORGE CHURCH: They're very closely related to the mammoths. Even though they don't look that way, they are genetically very similar.

TALITHIA WILLIAMS: And then he hopes the Asian elephant's new baby will come out woolier and more mammoth-like than this one. At least that's the plan.

Why would anyone think they could reverse evolution and bring an extinct creature back to life? The answer lies deep inside almost every living cell in your body, in your D.N.A. One of the wonders of D.N.A. is how simple it is: a double string made of four chemicals, usually known by their initials: A, T, C and G.

Strings of these letters form genes, the coded instructions that tell a cell to build specific proteins. Arrange the letters one way and you'll get keratin. It's not just a hair treatment; it's the main protein making up our hair, skin and fingernails.

Switch the order of the letters, and you could get ricin, a protein made in the seeds of a castor oil plant, and, to a human, extremely poisonous. D.N.A. and the order of its letters are the instructions that turn a fertilized egg into a flounder, a frog or a fly.

The quest to use D.N.A. to control and manipulate life began over 40 years ago, on creatures a whole lot smaller than elephants, in an attempt to treat a deadly disease.

In the 1970s, Herb Boyer and Stanley Cohen began using new D.N.A. technology to see if they could coax common E. coli bacteria into producing human insulin protein.

People with diabetes don't produce enough insulin to help their bodies absorb sugar and other nutrients and will die without injecting it. Before the 1970s, insulin was extracted from cattle and pigs. Unfortunately, insulin from these animal sources sometimes caused severe allergic reactions. But the Boyer team was about to change that.

Their idea was to engineer E. coli bacteria by first cutting its genetic material with enzymes and then inserting a synthetic version of the human insulin-coding gene into the gap. Amazingly, the altered bacteria not only copied the human gene whenever it divided, they produced human insulin, a lifesaver for diabetics ever since.

ARTHUR CAPLAN (New York University School of Medicine): I found it amazing, as a non-biologist, that you could trick a tiny microbe into making something that it doesn't naturally make and reorient it to make something that we want.

TALITHIA WILLIAMS: Here in a biochemical lab at M.I.T…

KRISTALA JONES PRATHER: We actually should go back and redo some of those things.

TALITHIA WILLIAMS: …Kristala Jones Prather will lead the team that is also altering the genes of microbes to make proteins and chemicals that are useful to us.

KRISTALA JONES PRATHER: You can actually look at those individual cells as little factories. If you shrunk yourself down to the size of a molecule, you would just see lots and lots of chemical reactions.

TALITHIA WILLIAMS: But you need trillions of organisms to produce enough of these tiny chemicals to be useful commercially. So, today, biotech companies use giant fermenters filled with microorganisms to pump out a slew of bio products, all thanks to our ability to manipulate D.N.A.

KRISTALA JONES PRATHER: The key observation that really fueled the entire biotech industry was recognizing that D.N.A. is really just a chemical, and the structure is what matters. And so it doesn't matter if that D.N.A. came from a horse or a mouse or something you dug off the bottom of your shoe, the D.N.A. is still just the D.N.A.

TALITHIA WILLIAMS: Today, production facilities not only make bio products, they make synthetic D.N.A. and can even process the four basic chemicals into an exact genetic sequence you can order online.

DREW ENDY: You'd go to a Web site for a company, a D.N.A. synthesis company, and you'd submit to that Web site the, the sequence of D.N.A. you want.

NILI OSTROV (Harvard Medical School): We can take the entire gene sequence and copy and then put it in an order sheet.

DREW ENDY: You can say T, A, A, T, A, C, G, A, C, T, C, A, C, T, A, T, A, G, G, G, A, G, A, give them a credit card number…

NILI OSTROV: …order this D.N.A.

DREW ENDY: They'll print that D.N.A., put it in an envelope and mail it to you.

NILI OSTROV: We get the gene back in a tube in about a day or two.

DREW ENDY: It's D.N.A. that is made from scratch, by the machine. This is a bottle full of the letter A. Not the letter in the alphabet, but the base of D.N.A. There's ten grams of stuff in here, and it costs about $250 for the bottle. There's enough material to make approximately 30 copies of every human genome on the planet.

RANA EL KALIOUBY: So, think about what this means: all the convenience of online shopping, just like I can custom-order a car. Do I want the silver or the red? Or build my own pizza: extra cheese, mushrooms, definitely not anchovies. Perfect.

Along with all this stuff you can buy online, amazingly, you can custom-order actual D.N.A. So now, with a credit card and a computer, not only can you build your own jeans, you can build your own genes.

TALITHIA WILLIAMS: Our ability to build and manipulate the genes that control life means we now have the power to remake life.

And this young scientist is trying to prove it, with one of the most daring genetic experiments on the planet. Kevin Esvelt wants to stop a growing menace on Nantucket and Martha's Vineyard, beautiful island communities off the coast of Massachusetts.

On the surface, you wouldn't notice anything especially scary on Nantucket. Tourists flock here, and others live year-round, to enjoy the beauty, fun and comforts of island life. What they don't come for, but often get anyway, is Lyme disease.

TIMOTHY LEPORE (Nantucket Physician): Devin, why don't you come on down.

TALITHIA WILLIAMS: Dr. Timothy Lepore is a 30-year veteran of treating Lyme disease on Nantucket.

TIMOTHY LEPORE: In the spring and summer on Nantucket, if I see something like that, that's Lyme disease.

TALITHIA WILLIAMS: Lyme is a bacterial infection that often starts with a rash, where a person has been bitten by an infected tick.

TIMOTHY LEPORE: You get rashes.

TALITHIA WILLIAMS: Most people can be cured with antibiotics that eliminate the rash, fever and joint pain within a few days.

TIMOTHY LEPORE: When we treated you, you got better?

PATIENT #1: Yep.

PATIENT #2: Then the next day, it had the ring around it.

TALITHIA WILLIAMS: But not everyone recovers so quickly.

TIMOTHY LEPORE: People that have had long-standing Lyme disease may have some persistent issues. If you wait, you can have delayed symptoms, like complete heart block, where your heart starts beating 20 to 30 times a minute. Or you can have a facial palsy, where it looks like one side of your face is paralyzed.

Come on in.

KEVIN ESVELT (Massachusetts Institute of Technology Media Lab): Lyme is the single most common infectious vector-borne disease in the United States. It's way more common than Zika, way more common than West Nile, anything like that.

The areas of Nantucket and Martha's Vineyard are number two and number three when it comes to incidence of tick-borne disease in the United States.

TALITHIA WILLIAMS: Kevin Esvelt is on a mission to eradicate Lyme disease, and, for him, these Massachusetts islands are the perfect places to start. This pocket of dense vegetation is typical of Nantucket and the rest of the northeast.

SAM TELFORD (Tufts University): Can't find an easy way out.

TALITHIA WILLIAMS: Sam Telford is working with Kevin. An expert on ticks and tick-borne diseases, Sam's diving into this brush, because he knows it's literally crawling with ticks for him to study.

Dragging a white furry cloth, Sam is hoping to catch ticks that think the cloth is an animal.

SAM TELFORD: Ticks are what we call "ambush" predators. They sit there on a blade of grass, and they've got their front legs sticking out, and then as you walk by, they'll latch on to something that they think is furry.

There is one here.

TALITHIA WILLIAMS: This is a tick in an early stage, when it's very tiny.

SAM TELFORD: No one who gets Lyme disease recalls that they were bitten by a tick, simply because of their small size. How on earth are you going to see something that small?

TALITHIA WILLIAMS: Humans get Lyme disease from ticks, but ticks are not born with Lyme bacteria. They get it by feeding on this innocent-looking critter, the white-footed mouse that carries Lyme bacteria in its blood. And another innocent-looking creature, the deer, is a crucial link in the chain of transmission to us.

Baby ticks will often feed on mice that are close to the ground, and this is when they get the Lyme bacteria. As the ticks grow, they will feed on other mice, deer or people, passing the Lyme bacteria with each bite. But only people get the disease.

A single deer is like an all you can eat buffet. They live in the woods and can't easily scratch ticks off, so females ticks become engorged, drop off, lay eggs, and the cycle starts again.

KEVIN ESVELT: The typical deer has several thousand ticks attached to it. And the females will each lay several thousand eggs. So, when you see a deer wandering around through the woods, you can think, "That is the walking equivalent of a million ticks in the next generation."

But people adore seeing deer and don't want them removed.

TALITHIA WILLIAMS: Could it be childhood memories of Bambi?

KEVIN ESVELT: It is Bambi. But we like seeing deer, so, because there are so many more deer than there have ever been before, historically, there are many more ticks than there have ever been before.

TALITHIA WILLIAMS: Now, deer shed ticks in our lawn clippings, garden plots, recreation areas. And if they carry the Lyme bacteria, they can give it to us. Here on Nantucket 40 percent of residents have caught Lyme disease.

And it's not the only tick-borne disease they have to worry about.

SAM TELFORD: There's an infection called "Nantucket fever" or "human babesiosis," which was first identified here in 1969. It's a malaria-like infection, and it, it actually kills people.

TALITHIA WILLIAMS: There are four serious tick-carried diseases on the island, with Lyme by far the most common. But it's not just these tiny islands. Mice, deer and ticks have spread Lyme disease throughout the northeast U.S. Almost anyone in the region who ventures outdoors, not just into the woods, but in suburbs, too, is putting themselves at risk.

For Kevin Esvelt, it's a risk people should not have to take, especially with their kids.

KEVIN ESVELT: I'm from the west coast, and there, we have ticks, but they're so rare that I spent my childhood running around through the woods and never once got bitten by a tick, not once.

Noah, down the slide. Come on, I'm going to catch you. Whoa!

I have two kids, and it's just terrible that we have to be wary of them just running in the woods. So, the notion that you can wander out here through some of the worst areas and end up with lots of ticks on you is just, well, it's frankly horrifying.

SAM TELFORD: All right, so I have 40 traps out on this site.

TALITHIA WILLIAMS: Kevin has a plan to make the outdoors safe again.

KEVIN ESVELT: Mice all seem to be wary today.

TALITHIA WILLIAMS: He believes he can get rid of Lyme disease by genetically altering the white-footed mice that carry it. And if that goes well, he hopes to edit their D.N.A., so they could resist ticks entirely.

SAM TELFORD: Ahhh, looks like we've got one to take back.

KEVIN ESVELT: Enlisting mice in the war against tick-borne disease would just be an amazing proposition.

SAM TELFORD: I'm counting 18 on the ears.

TALITHIA WILLIAMS: The number of ticks is astounding, especially on its ears. And if this mouse has the Lyme bacteria, all the ticks will become infected and can transmit the disease to us.

Kevin's plan is to make the mice resistant to Lyme bacteria, with the help of genetic engineering's most exciting and powerful tool, CRISPR.

ANDRE FENTON: CRISPR stands for: Clustered Regularly Interspaced Short Palindromic Repeats. That's why it's just called "CRISPR."

First discovered in bacteria, CRISPRs are like bacterial immune systems. They have two key parts: a destroyer protein, like one called Cas9, and a piece of R.N.A. that matches viruses that previously infected the bacteria. If the same virus were to invade again, the R.N.A. would recognize the invader's D.N.A., attach itself to its old enemy, and its Cas partner would slice the virus' D.N.A., destroying it.

A few years ago, some researchers realized they could use CRISPR to edit the genome of any living organism. Here's the idea: say I have a stretch of D.N.A., maybe a part of a gene I'd like to change. If I know the sequence of letters there, I can build a CRISPR that carries a matching code. Once inside the cell, CRISPR will scan the D.N.A. until it finds that exact spot, and when it does, it slices the D.N.A. right there.

Now I have a broken gene, but it turns out I can insert a new sequence into the gap. And that makes CRISPR potentially an extremely powerful tool.

BETH SHAPIRO: CRISPR-Cas engineering is much faster. It's much less expensive, and it's much easier to make those changes you want to make.

KRISTALA JONES PRATHER: The really significant revolution with CRIPSR-Cas9 is that, as far as I can tell, it pretty much works in any organism that you try it in.

TALITHIA WILLIAMS: And M.I.T.'s Kevin Esvelt wants to use CRISPR to change the D.N.A. of mice and make them immune to Lyme bacteria.

KEVIN ESVELT: The original idea that sparked this whole process was very simple.

Hey.

LAB TECHNICIAN: Hi.

KEVIN ESVELT: Animals like us, and also the mice, when we get sick with something, our immune systems evolve an antibody, often lots and lots of antibodies, that are really, really good at telling the immune system, "This is the enemy, kill it."

TALITHIA WILLIAMS: But these antibodies do not get passed on to our children, so we need vaccines to give us antibodies against certain diseases. But there is no human Lyme vaccine. And even if there was one for mice, he couldn't just line them up for shots. So, instead, Kevin wants to give them a genetic vaccine. Here's how that would work: first, Kevin, with the help of Sam Telford, infects mice in the lab with Lyme bacteria. These mice quickly develop robust, Lyme-resistant antibodies. Next, the team deciphers the genetic code that can create those antibodies. They make this antibody gene in the lab and inject it, along with CRISPR genes, into the developing sperm cells of Sam's lab mice. There, CRISPR would clear the way for the new gene to slide into the mouse's genome.

Now, if an engineered male mates with a wild female, roughly 50 percent of their babies, boys and girls, will inherit the Lyme-resistant gene and begin spreading it to future generations of mice. That is if Kevin's plan works.

But before he can even try, he'll need Nantucket residents to approve the release of genetically modified mice, something many people here worry might backfire, like the disastrous cane toad experiment.

Cane toads were introduced to Australia in the 1930s, to help kill off sugar cane beetles. But instead they became a biological wrecking ball. A foreign species with no natural predators, they quickly overran the country. Poisonous to animals, they've killed countless pets and native species, disrupted key parts of the country's ecosystem, and they are now almost impossible to get rid of.

The mice used in Kevin's experiment will be native, not foreign, but some people worry that genetically modifying animals could spell trouble.

TIMOTHY LEPORE: If you fool with Mother Nature, very often it doesn't turn out well. So, are we going to have mice the size of boxer dogs? I don't know.

TALITHIA WILLIAMS: As Kevin releases a wild mouse caught earlier, he hopes that someday the little creature jumping away will be resistant to Lyme disease. But to get that far, he will need the island's complete trust. And the jury is still out. Will people's fear of genetic engineering prevent Kevin from using this controversial science?

ELEONORE PAUWELS: (Wilson Center): You know, this is a, a technology too powerful for humankind to refuse. It's going to help us transform not only our bodies and our genes, but can give us a chance to actually play a role in our own evolution.

TALITHIA WILLIAMS: George Church is certainly playing with evolution by attempting to de-extinct a woolly mammoth, but why does this gene giant even want to do this?

BETH SHAPIRO: George is one of those people in science who is just larger than life. He just wants to be doing those most exciting projects at the cutting edge of whatever it is.

GEORGE CHURCH: Wow, that is the coolest virus I have ever seen.

TALITHIA WILLIAMS: George's lab is renowned for stretching the limits of genetic engineering, from experiments using pigs to grow human organs for transplantation, to using bacterial D.N.A. to encode and store data and even digitize movies. But the woolly mammoth would be his greatest accomplishment yet.

RANA EL KALIOUBY: Seeing a real mammoth again would be amazing, but what about saber-tooth tigers or giant dodo birds, even flocks of passenger pigeons.

Bringing back extinct creatures wouldn't just be cool, we could see how these magnificent animals once lived and maybe find out how to save today's creatures from going extinct, which is exactly what George Church wants to do for the Asian elephant.

TALITHIA WILLIAMS: George's plan is to combine the genes of a woolly mammoth with those of Asian elephants, because making them mammoth-like might save them. Hunted for their tusks and chased from farmlands, Asian elephant numbers are shrinking. But George has a possible solution.

GEORGE CHURCH: If you gave them access to one of the largest ecosystems on the planet, which is the Arctic tundra, where their very close relatives used to roam, that would probably save the species.

TALITHIA WILLIAMS: There's plenty of open, fertile space in the tundra, but it's too cold for warm-weather elephants to survive here. So, George's resurrection plan begins with genetically winterizing Asian elephants to become more like woolly mammoths, who loved the cold.

The team first identifies the specific genes in modern animals that code for things like fat or thick hair. Then they look for their genetic counterparts in decoded mammoth genomes. Once they identify the mammoth's "cold" genes, they make them synthetically and insert them into living cells taken from an Asian elephant to see if they work.

BOBBY DHADWAR (Harvard Medical School): What we're seeing here is green cells. These are elephant cells that we've introduced mammoth D.N.A. into. The brighter the green that we're seeing means the more D.N.A. is taken up.

TALITHIA WILLIAMS: In the lab, they've edited about 35 functioning woolly mammoth genes into the Asian elephant genome. This is a good start for making a semi-woolly mammoth, but it's the next step that will be the most challenging.

BETH SHAPIRO: There is a huge difference, obviously, between a cell growing in a dish in a lab and a baby mammoth wandering around.

How do I take that cell and turn that into an actual living breathing organism?

TALITHIA WILLIAMS: They could try and fertilize the egg cell of a captive Asian elephant with Wooly Mammoth genes, but this is difficult.

BETH SHAPIRO: It's very hard for them to get pregnant in captivity. The pregnancies often don't go to term. And this is probably has to do with the psychology of being in captivity.

TALITHIA WILLIAMS: And performing such an operation on an endangered species like this may simply be too great a risk. So, George is studying mammals like the platypus and spiny anteater whose babies develop outside a mother's body in an egg.

RANA EL KALIOUBY: Could he possibly engineer a living mammoth this way? Can you imagine a baby woolly mammoth hatching out of an egg? Really? Not even George has figured out how to do this. And then what would this sort of mammoth be like?

ARTHUR CAPLAN: I think you're going to get a creature that's sort of a pseudo-mammoth, not quite the same makeup. So, I think you're going to get a sort of echo of the animal that once was, but not a replica.

BETH SHAPIRO: So, even if we could get to the point where we could transform this elephant to a living breathing baby mammoth, a question that I have really is, "Should we?"

We know that elephants are very social creatures. They live in herds, interacting with each other. Unless we can get this down in such a way that we can do many different individuals at a time, you're still just going to have one generation to start with, and that just seems kind of unfair.

TALITHIA WILLIAMS: Although we may never see a mammoth, George's efforts to identify and make more resilient animal genes may have a hidden benefit.

BETH SHAPIRO: This technology, the ability to take genes from the past and put them into species that are alive today has tremendous potential as a new tool for conservation. Many of the endangered species and populations have very little genetic diversity, and that means that they have very little ability to adapt to rapid climate change, or if a disease comes in, and wipes out most of the individuals who are there. We can use this technology to help species that are on the brink of extinction today.

TALITHIA WILLIAMS: But what about us? We've known for decades that mistakes in our own D.N.A., sometimes the switching of just a letter or two, can lead to life-threatening problems. For example, an A instead of a T on just one of our genes causes sickle cell disease, a lifelong blood disorder.

So, is it possible to harness new technologies to rewrite our own genetic code? Could we use this power to save lives?

Doctors and researchers have been trying to do this for decades, but with limited success. Dr. David Williams of Boston Children's Hospital has participated in several gene therapy trials that invariably ended in disappointment.

DAVID WILLIAMS (Boston Children's Hospital): We saw a real need for this technology to be developed. People were then disappointed, including scientists when the hype didn't' get realized.

TALITHIA WILLIAMS: To make matters worse, in 1999, 18-year-old Jesse Gelsinger entered a trial for a genetic liver condition. He only had a mild form of the disease, but tragically, the gene therapy ended up killing him.

DAVID WILLIAMS: This set the field back enormously, and it's taken a long time for the field to recover from those setbacks.

CHRISTINE DUNCAN (Boston Children's Hospital): This is the family we just met this morning. He's 7-years-old, but wasn't diagnosed until August.

TALITHIA WILLIAMS: Today, Dave Williams heads a new gene therapy trial that aims to cure a devastating childhood disease…

CHRISTINE DUNCAN: So, he's had febrile seizures since he was eight-months-old.

TALITHIA WILLIAMS: …a heartbreaking killer called "cerebral adrenoleukodystrophy," or A.L.D., and the stakes couldn't be higher.

Brian Rojas and his mother Lillianna are just about finished trimming their Christmas tree, but Brian's brother Brandon cannot join them. Three years ago, the two boys were inseparable; their family full of love and joy.

LILLIANA ROJAS (Mother of Brandon Rojas): Are you ready? Are you ready?

TALITHIA WILLIAMS: Now, at age nine, Brandon still gets the love, but A.L.D. is devastating his mind and body.

LILLIANA ROJAS: All right, come on.

TALITHIA WILLIAMS: He can do nothing for himself anymore.

DAVID WILLIAMS: Adrenoleukodystrophy is a genetic disease, and it's what we call "x-linked," which means it occurs mostly in boys. And the typical history that we hear from families is that they have a perfectly terrific young boy who, at the age of five or six, suddenly begins to have developmental problems.

LILLIANA ROJAS: Brandon started with drooling, and we thought it was because he lost his front tooth, and we didn't think anything else of it. And little by little, he started losing his vision.

CHRISTINE DUNCAN: They may have change in their vision. They may have change in their hearing. They'll have change in their ability to communicate or speak with the family. And it all ends up, ultimately, with complete devastation and death.

TALITHIA WILLIAMS: Dr. Christy Duncan has watched the inexorable decline of many A.L.D. boys, because of a mutation on a gene called ABCD1 that affects microglial cells in the brain.

CHRISTINE DUNCAN: These are cells in the brain that are responsible for maintaining a healthy environment around some of the neurons. And so, what you'll see over time is inflammatory lesions in the brain.

TALITHIA WILLIAMS: On M.R.I.'s we can see these lesions rapidly increase over time, as the disease destroys the brain.

Unless you know there is A.L.D. in your family, the disease comes as a complete shock.

HEATHER COOKSON (Mother of Jerry and Ricky Cookson): It's heartbreaking to find out that unknowingly, I passed this gene and ultimately disease to my children.

TALITHIA WILLIAMS: Heather Cookson's son Jerry is 12, older brother Ricky, 14. Ricky was eight, when persistent headaches convinced Heather to insist he get an M.R.I.

HEATHER COOKSON: They found a lesion in Ricky's brain during that M.R.I. We just thought it was headaches; never thought it was going to be a life-changing disease that he was going to have.

TALITHIA WILLIAMS: Children like Ricky can often be saved with a blood stem cell transplant. These cells originate in bone marrow and can become all blood cell types. But why new blood cells stop the progress of A.L.D. in the brain is somewhat mysterious.

CHRISTINE DUNCAN: This is a disease of brain cells. These are not the same cells, and so it can be hard to understand why on earth that works.

TALITHIA WILLIAMS: For his transplant to work, Ricky needed a good genetic match, like his little brother Jerry. But Jerry also carried the faulty gene so could not donate. Fortunately, Ricky found an unrelated matching donor and after the transplant and chemotherapy, he is now doing fine.

But by the time Brandon Rojas was diagnosed, his A.L.D. had progressed too far to even try a transplant. And the news hit hard.

LILLIANA ROJAS: I couldn't accept the fact that they said there is no cure. We, I I couldn't accept it. And that's when my whole world just fell down, and I didn't know how to react.

CHRISTINE DUNCAN: It's terrible. It's a tragedy. And the only, even if you can call it, sort of, bright spot of that tragedy: his younger brother Brian was identified because of the older brother's disease.

LILLIANA ROJAS: Say hi, Brian.

BRIAN ROJAS: Hi.

TALITHIA WILLIAMS: It wasn't guaranteed that having the bad gene would give Brian the deadly form of the disease, but Lilliana was worried.

LILLIANA ROJAS: We were hoping he was fine. We thought you know, "Please God, don't let him have the same."

BRIAN ROJAS: (Reading) …he became a hero, Dr. Stephen…

TALITHIA WILLIAMS: But about a year later, a small lesion appeared on Brian's M.R.I. Worse, there were no matching donors for an immediate transplant, and his A.L.D. was progressing by the day. So, when a new gene therapy trial opened up, Lilliana jumped at the opportunity.

LILLIANA ROJAS: One of the things that the doctor said was, "We can save him."

HEATHER COOKSON: Do you want to go up there?

TALITHIA WILLIAMS: Heather Cookson also learned that her younger son Jerry, like his older brother Ricky, had developed A.L.D.

CHRISTINE DUNCAN: Follow my finger with your eyes.

HEATHER COOKSON: I got hit with a ton of bricks after his M.R.I.

TALITHIA WILLIAMS: But Jerry would soon join Brian Rojas and 15 other boys in a gene trial that could save their lives, and Jerry Cookson was up for the challenge.

Therapy begins by collecting stem cells from the boys' blood, then taking them to a cleanroom, where the genetic engineering begins. The doctors need to insert a healthy version of the gene into the boys' stem cells. To do this, they rely on a virus that's incredibly adept at invading cells: H.I.V. The lethal virus has been altered so it can't make anyone sick, but it's still able to enter cells and do what viruses always do, insert its D.N.A. into the host's cell. Only this time, the D.N.A. carries the healthy gene that will hopefully stop the spread of A.L.D.

DAVID WILLIAMS: These viruses sort of say to the cell, "These are your genes. You start producing proteins based on my genetic makeup."

TALITHIA WILLIAMS: Researchers have been editing with viruses for decades, and they're still relying on them for human gene therapy while the newer CRISPR editing is being perfected. As their cells are being engineered, the boys undergo intense chemotherapy to make room in their bone marrow for their new stem cells to grow.

Then it's time for reinfusion and hope for success.

JERRY COOKSON: I started chemotherapy. Ten days after that, on May 19th, I got my cells back into me. And it's really kind of anticlimactic when you think about it.

TALITHIA WILLIAMS: But Jerry could not feel what was going on inside his body.

The new stem cells multiplied and began circulating in his bloodstream. As they reached his brain, some changed into new glial cells, now with the healthy gene. But would this be enough to stop the progress of the disease?

After three months, Jerry Cookson was released from the hospital and is showing no A.L.D. symptoms. Of the 17 boys who entered the trial, 15 completed the therapy and so far, all are doing fine.

JERRY COOKSON: So, I think it's kind of cool that I'm, like, one in 16 or 17 people that did this treatment. It's a new treatment that could change a lot of other people's lives.

CHRISTINE DUNCAN: He has been stable. He's in school, he plays soccer. He is perfect.

TALITHIA WILLIAMS: And for the therapy team, this has been the experience of a lifetime.

CHRISTINE DUNCAN: I truly feel so incredibly lucky to be at this end of it. We're finally able to take the fruits of years and years of people's work and treat these boys. And they are going to school, and they are living proof of what science can do. And it is really remarkable.

HEATHER COOKSON: We're extremely lucky. There are some families out there that aren't as lucky as our family.

BRIAN ROJAS: He wears a black costume.

TALITHIA WILLIAMS: For the Rojas family, the end of the trial is bittersweet. Since Brian received gene therapy, he is healthy and seems to be headed for a normal life, while his brother Brandon is slipping away. But to Lilliana, Brandon is a hero.

LILLIANA ROJAS: Because of Brandon, Brian was diagnosed early. Brandon saved his little brother.

TALITHIA WILLIAMS: A new gene therapy, decades in the making, saved Brian Rojas. Could this be a sign we've turned the corner on gene therapy cures?

DAVID WILLIAMS: It is literally going to be hundreds of diseases that we'll now be able to approach. The future of genetic therapy is actually here.

TALITHIA WILLIAMS: For anyone touched by genetic disease, new breakthroughs could not come quickly enough, and many hope genetic engineering could go even further. But if we can fix mistakes in someone's D.N.A., could we do that even before they were born?

We have the ability to alter the D.N.A. inside human embryos and in the germline cells that make them. The big question is should we? And why is even talking about this so controversial?

ARTHUR CAPLAN: I think the driving fear of the germline engineering, fixing things across generations is the slippery slope. A lot of people would say, "Yeah, okay, you want to go out and fix Tay-Sachs disease that kills people? Hurray."

You want to fix deafness. You want to get rid of short stature. Where does that all end? Aren't we going to wind up doing things like, "I want my kid to be stronger, smarter, faster."

TALITHIA WILLIAMS: In other words, editing embryos not to cure a disease but to enhance abilities and make designer babies. There's been experimental efforts at curing genetic diseases in embryos, but the fear this could lead to designer babies is so strong, most countries prohibit it entirely. And the U.S. government won't fund it. But are those fears justified?

SHOUKHRAT MITALIPOV (Oregon Health & Science University): The complexity of how to make designer babies is such a big deal, we don't even know what genes or how many genes would make a child taller or smarter.

ARTHUR CAPLAN: It's one thing to say, "I'm going to repair a single error that causes a particular genetic disease." It's another thing to say, "I've got to insert 500 genes, in order to make your memory enhanced." The whole thing is hard to do.

TALITHIA WILLIAMS: But our genetic knowledge is increasing, and it certainly seems possible that one day we will be able to design our babies.

ARTHUR CAPLAN: In a competitive market society, you see people showing up at I.V.F. clinics saying, "You know, we're having trouble conceiving, but as long as I'm here, could I get a 6-foot-7 Ukrainian mathematician donor, because that's what we wanted." "Red headed, is that possible?"

Down the road, long-term, are we going to see enhancement or improvement anyway? Yes.

TALITHIA WILLIAMS: But if we do go down this road, where will it end?

MARCY DARNOVSKY (Center for Genetics and Society): When we start doing really biologically radical things, we could see some terrible health consequences develop when the child is two years old, 20 years old, or when that child has children of his or her own.

We just don't know what the unintended consequences might be and if anybody who would be contemplating using a technology like this should really ask themselves whether it's worth the risk.

TALITHIA WILLIAMS: The power of genetic engineering to sculpt ourselves and the natural world does bring a burden of risk.

And although Kevin Esvelt is confident his engineered mice will only reduce Lyme disease and not bring harm to Nantucket's ecosystem, he also knows that absolute certainty and genetic engineering do not go together.

KEVIN ESVELT: I worry every day that I might be missing something profound about the consequences of what we're developing.

TALITHIA WILLIAMS: At a town hall meeting, Kevin assures residents he will be taking a go slow approach…

KEVIN ESVELT: Frankly, what we're talking about here is altering a shared environment.

TALITHIA WILLIAMS: …and that he could halt the experiment if problems appear. Most importantly, they would determine if the mice would ever get released here.

KEVIN ESVELT: To be clear, this project will only move forwards if the community supports it at every step of the way.

TALITHIA WILLIAMS: He tells them he would first perform a field test on an isolated island to check that the new gene is working and the altered mice are causing no problems. Only then would he propose releasing them on Nantucket.

KEVIN ESVELT: Once you have those, then…

TALITHIA WILLIAMS: But for his new gene to spread throughout the mouse population, he would need to release a lot of engineered mice.

KEVIN ESVELT: It might mean releasing say a hundred-thousand mice on Nantucket.

TALITHIA WILLIAMS: It would take that many to spread the Lyme-resistant gene effectively.

RICHARD COOPER (Nantucket Resident): What happens to the actual population, the mouse population, itself? I mean that's just going to keep growing and growing and growing.

SAM TELFORD: Actually, no.

TALITHIA WILLIAMS: Although residents are concerned by the numbers, Sam Telford assures them the mice population will stay in check.

SAM TELFORD: Something is out there that's regulating them. Disease is regulating them. There's a, a mite, a mange mite that is regulating them.

TALITHIA WILLIAMS: But even one G.M.O. mouse is still alarming for some.

DANICA CONNERS: This is rapid, rapid man-made evolution.

ROBERTO SANTAMARIA (Nantucket Resident): Some people think that genetically modified organisms should never be done. They think that people like Kevin are playing God.

DANICA CONNORS: We don't know what effect it's going to have 15 years, 20 years, 25 years down the line.

TALITHIA WILLIAMS: But Kevin's cautious, open science approach seems to be winning the day.

KEVIN ESVELT: If you were to run these kinds of experiments the way science is traditionally done, behind closed doors, you'd be denying people a voice in decisions intended to eventually affect them.

TIMOTHY LEPORE: Devin, why don't you come on down?

TALITHIA WILLIAMS: Islanders have given Kevin the go ahead to engineer the mice. But with a Nantucket release years away, there are no hard choices for them to make, yet.

TIMOTHY LEPORE: So, how are you doing?

TALITHIA WILLIAMS: Still, residents here are so fed up with Lyme disease, if the field test does go well, Kevin's grand experiment could go all the way.

And if he stops Lyme here, what diseases would he target next? Could Kevin and other researchers one day engineer mosquitos to halt the spread of deadly malaria?

KEVIN ESVELT: If we could just go in there and change the mosquitoes so they can't transmit malaria, or better yet, someday, so that they just don't want to bite people, that would be the most elegant solution to a problem.

TALITHIA WILLIAMS: Kevin Esvelt is walking in the footsteps of those early pioneers who engineered bacteria to make insulin for diabetics. Today, we have the capacity to alter the genomes of every living thing. So, the potential rewards, and the risks, of genetic engineering have never been greater.

ELEONORE PAUWELS: A few decades ago, the changes we would impose on biology were very much incremental. They were little steps. But now we could drastically accelerate the engineering of our genes, our bodies and even our ecosystems.

TALITHIA WILLIAMS: Despite all we can do, there's still one thing we can't do.

KRISTALA JONES PRATHER: We can't create life. We can't create a cell from scratch. We can take an existing cell, and we can make so many changes to it that it looks nothing like what it started out as, but we have to start from something that's already living in order to end up with something that's living.

TALITHIA WILLIAMS: So, right now, we can't make life, but we can radically change it in ways that will impact our own evolution and the future of the planet. The question is: will we use this power wisely?

Credits

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This program was produced by WGBH, which is solely responsible for its content. Some funders of NOVA Wonders also fund basic science research. Experts featured in this film may have received support from funders of this program.

Original funding for this program was provided by the National Science Foundation, the Gordon and Betty Moore Foundation, the Alfred P. Sloan Foundation and the John Templeton Foundation.

This material is based upon work supported by the National Science Foundation under Grant No. DRL-1420749. Any opinions, findings, and conclusions or recommendations expressed in this material are those of the author(s) and do not necessarily reflect the views of the National Science Foundation.

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Participants

Arthur Caplan, George Church, Danica Connors, Richard Cooper, Marcy Darnovsky, Bobby Dhadwar, Christine Duncan, Rana el Kaliouby, Drew Endy, Kevin Esvelt, André Fenton, Kristala Jones Prather, Timothy Lepore, Shoukhrat Mitalipov, Nili Ostrov, Elenore Pauwels, Roberto Santamaria, Beth Shapiro, Sam Telford, David Williams, Talithia Williams

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