Life from scratch

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1:21There's this saying about the difference between biology and chemistry. Yogurt can make more yogurt, but shampoo can't make more shampoo. That is to say, yogurt has a community of living microbes or tiny organisms. Some yogurt cultures can live for decades. And it takes just a little bit of yogurt to turn milk into more yogurt. Shampoo, on the other hand, is just shampoo. It's inert. It's dead. It doesn't make more of itself. For now. That's what we need to do. You know, yogurt can make more yogurt. Why cannot shampoo make more shampoo? Kate Ademalo wants to make chemistry look a lot more like biology.

2:11And enable anyone in all parts of the world to refill their own shampoo bottle. They shouldn't have to order their shampoo from the five places in the world that make shampoo. Again, using shampoo as just an analogy. Shampoo as an analogy for all sorts of chemicals that we rely on every day. Medicines, food, fuel, materials. Today, making these things in a chemistry lab is messy, wasteful, and sometimes toxic. Instead, the idea here is to harness life to help us grow what we need. During COVID, for some reason, we rediscovered the bread making. Everyone was having their own sourdough starter. My sourdough starter, his name was Hank, and I was making my own bread for a while.

2:58And that should be possible. Everyone should have their own hank, their starter of shampoo, bread, all the other essential chemicals that we need. Kate wants to radically tinker with cells so they can make all those helpful chemicals in a renewable way. You can draw a direct line from the work I'm doing towards something that will actually change someone's life. Create a new drug and create new technologies that will help our economy, that will help the climate. That's the driving goal. But before scientists like Kate can harness this power of biology, first they have to understand it. Because how life works on a cellular level is still a mystery.

3:44We don't really know what makes cells alive, what animates them, what drives them. And we have to understand this to reach Kate's vision for the future. Cells are staggeringly intricate, and the more we dig in for answers, the more questions we find. One of the things that distinguishes biology from chemistry and physics and other science is its incredible complexity. John Glass, Kate's mentor, has been studying the inner workings of biology for decades. Our goal has been to understand life. What is life, right? Right now, any living cell that we know of, it's too complex. We don't understand where every molecule of that cell goes.

4:33You go to the doctor and they think they know what's going on in your body and they tell you, take this drug, that drug. But in reality, of the kernel of life, there are potentially things that cells do, essential tasks necessary for life that we're completely oblivious to. John and Kate are some of the leading voices in synthetic cell biology, a field where scientists focus on engineering life at its most fundamental levels. So as one of the founders of the field and its new rising star, together, John and Kate are pushing to figure out what makes cells tick with, as they see it, the future of our health and the health of our planet at stake.

5:21This is the beginning of our three-part series, Life from Scratch. I'm Meredith Hodnott, and this is Unexplainable.

5:44All life on this planet is related. Every living cell in every living thing. From a deep sea bacteria colony to your next door neighbor. All of those cells came from another cell. A long, unbroken lineage going back billions of years to the very origins of life on Earth. This is our tree of life. This is what it means to be alive here. For scientists trying to understand cells today, that means unwinding billions of years of these evolutionary tangles, all to figure out what's absolutely necessary for life. Science has always advanced using simple systems. Scientists, as far back as the 1930s, had aspired to have this simplest of all organisms, to use this to understand biology.

6:48And by the simplest of all organisms, John means an organism with the smallest possible genome. A genome is like the instruction manual, teaching a cell step by step what it needs to do to live. Each gene or combination of genes gives the cell an instruction, and those genetic instructions are written in DNA. In general, the smaller the genome, the fewer instructions it needs to live, and so the simpler the organism. For context, complicated human beings, we have about 20 ,000 to 30 ,000 genes in our DNA. Something smaller, something simpler, like an E. coli, has only about 4 ,000 genes. John spent his early career studying the DNA of some of the simplest organisms known to science.

7:43A type of single-cell bacterium, a kind of microbe, called mycoplasmas, which can have around a thousand genes or even fewer. They don't make anything except more mycoplasmas, so this lets them have exceedingly simple genomes. You can find them in lots of places, like the eyes and lungs of animals like goats. Or in the case of John's personal favorite mycoplasma. I joke that this was a marine bacterium because it was originally discovered in the urogenital tract of a British marine in about 1980. Uncomfortable for the marine, but a boon to science, helping researchers find the very limits of genetic simplicity.

8:33But how simple could a cell get while still keeping that mysterious spark of life? That's what John wanted to make. A simplest of all organisms, a minimal cell. So in 2003, John teamed up with some of the most famous biologists of the day. J. Craig Venter led the world in a number of amazing discoveries about biology changing the way science is done globally. An iconoclast with a brilliant mind and an outsized ego who has flaunted the staid scientific establishment at every turn. Craig had just made headlines all over the world for helping to decode the human genome. Dr. Craig Venner, I thank you, Craig, for what you have done to make this day possible.

9:28And now he was assembling an all-star team of researchers, including a Nobel laureate, to start making this dream of a minimal cell into reality. Is this like joining the Avengers or something? Were these some of the biggest names in biology at the time? Oh, yeah, these were heroes of mine. And what they really needed was a mycoplasma expert. And I fit that bill. So John joined what would later be called the J. Craig Venter Institute, or JCVI. Their plan was to get down to a genome even simpler than a mycoplasma, something way simpler than anything found in nature. But at this point, they couldn't manipulate the natural genome inside the cell.

10:16So they decided to make their own synthetic version in the lab. That way they could edit it however they wanted. But a lab-made synthetic genome wouldn't be able to tell them anything unless they could get it inside of a living cell and see if its instructions kept that cell alive. It was the 2000s, so they talked about these experiments in computer terms. Like the DNA was the software, the code programming the cell and telling it what to do. And the cell itself was the hardware, the physical computer executing that code. Except there's no downloading a new operating system update for a real-life cell in a Petri dish.

11:02So it was John's job to see if it was even possible to transplant a whole DNA genome into a living cell. John and his team tried different techniques and different combinations of natural mycoplasmas, but the cells kept dying. We're trying everything. One postdoc in particular, Carol Letig, spent two years on this. Nothing was working and nothing was working. And she came into my office one day and said, I want to quit. I want to go home. I'm tired of this. This is not working. And I talked her into going back into the lab. And the next day, she comes into my office bringing plates that showed two colonies of a successful transplant.

11:53This was a eureka moment. For the first time, the cells with the transplanted DNA didn't die. They grew. They flourished into a colony that was big enough to see without a microscope. And John and Carol knew that the transfer had worked because they had added in a gene to the new DNA that turned the cells blue. The colonies, they're blue. They're gorgeous. They look like fried eggs. She had gotten it to work. They were on the right track. The transplanted DNA worked, even though it wasn't original to the cell. It coded for proteins and it kept the cell alive. With this crucial DNA transplantation technique, the JCVI team were able to take their lab-made version of a mycoplasma genome and transplant it into a living cell.

12:50Today we found one blue colony, and we believe that this is our first synthetic cell. It's alive! This was the first time in history that a natural living cell, a cell from that long, unbroken lineage of cells going back to the very origins of life on Earth, was kept alive by a synthetic genome. All the genetic instructions that let these cells grow, thrive, and divide were made by human technology. For the first time, they have produced a living cell in which the active DNA was put together by computers. We have a biological self-replicating organism whose parent was a computer file, an email attachment, if you will.

13:37It's a world first, a living cell driven by synthetic DNA code put together by a computer. This new cell, nicknamed Cynthia, is a milestone for science. And if you believe the razzmatazz, the dawn of a new era. That sounds mind-boggling. This is Kate again, John's future mentee. She was getting her PhD at the time. And I was not in synthetic biology back then. But I was following it really closely because they have proven that you can chemically synthesize a whole genome, a genome of an organism. And then not only admire it because it's pretty, you can actually use it. It showed us that there is nothing magical about biology.

14:22There is no magic secret life force that makes cells tick. And that kind of sounds sad, but it's actually good from our point of view, because it gives us hope that we can truly understand biology. They named the cell JCVI-SYN 1.0, their starting point. The synthetic mycoplasma genome had about 900 genes, a lab-made copy of the mycoplasma's natural DNA. And now the JCVI team could push farther than nature had ever gone. What was the absolute simplest a DNA genome could be and still keep a cell alive? When they broke into that uncharted territory, what they found was more bizarre than they could have ever imagined.

15:13That's after the break.

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18:29A DNA strand like me is a blueprint for building a living thing. Deep inside the JCVI synthetic cell genome, there is a watermark. a kind of copyright or patent written into the lab-made DNA itself. They did this so that they could tell the difference between their synthetic cell and natural ones. But in this case, they also decided to have a little fun with it. So they inserted a secret message. It says, prove you've decoded this watermark by emailing us and has a link to their email address in the DNA of a living cell. But this watermark also included a lot more. It had the names of all the people working on the project.

19:18It had quotes from Robert Oppenheimer, from James Joyce. Oppenheimer, James Joyce. Oppenheimer, James Joyce. And I'm sorry, I forget the other one. I'm embarrassed. The last quote is from Richard Feynman. Feynman wrote, what I cannot build, I cannot understand. And we made it, I cannot understand what I cannot build. So we got that wrong, but we went back and fixed it. It's no accident that the JCVI team saw themselves in the quotes of not famous biologists, but famous physicists. Oppenheimer and Feynman both worked on the Manhattan Project and both famously wrestled with how they ushered in the nuclear age by studying matter at its most fundamental levels.

20:10Scientists use the hydrogen atom to understand the nature of matter. The hydrogen atom, the simplest of all atoms. What is true for hydrogen is true for all matter. And so using the hydrogen atom is what has led to our fundamental understanding of matter and chemistry. This was the same motivation driving John and the JCVI team, essentially applying the same logic to a different field. The hydrogen atom of biology. But like the physicists they quoted, they didn't know what they'd discover when they probed the foundations of existence.

20:57Imagine you wanted to figure out how a car works. Even a very simple car has a lot of extra stuff. GPS and entertainment systems and seat warmers. None of those extras will tell you how the car actually works, though, how it drives down the street. But if you can strip away all the non-essentials, throw out the air conditioning and the seatbelts and the windshield wipers until you get to the point where if you throw out just one more thing, the car won't drive anymore. Then you could study what is essential to making a car run without any of the bells and whistles. You'd have a minimal car. Mycoplasmas were a good start, training wheels to make sure that they could make a synthetic genome or instruction manual for life and successfully transplant it into a living cell.

21:52Now they could use the synthetic DNA that they already made, that they knew worked, and whittle it down by process of elimination. For years in the lab, they tried new designs, throwing out non-essential genes and testing whether their genomes could keep cells alive. And finally, they had it. A minimal cell. Just under 500 genes. So it was seven years to get to the point where you could make a man-made version of a naturally occurring cell. And then another six years to strip that down into as simple a man-made genome as humanly possible. Now, so the genome is about 85 % a century. They could have gone further.

22:45They could have thrown out even more genes. And if we were trying to get into Guinness Book of World Records, we might have done that. But we had something that was really tractable, and it worked within days. Scientists all over the world were contacting us, saying they want to work with us. They would like our cell to use it to investigate the first principles of biology. If you had started with a different microbe, would you have ended up with a different minimal cell? Absolutely. So how does that interact with this idea of first principles of life and trying to get down to the essentials? Sure.

23:28That's an excellent question, Meredith. So the way we were thinking about this is not so much what are the essential genes for life. What we were trying to answer is what are the tasks that a cell has to do to be alive? So going back to the car metaphor, I can strip down my Subaru and you can strip down your Tesla and we'd end up with different minimal cars. There are different parts that are essential to making both of those cars run. But whether your minimal car has a gas tank or a big battery, the problem those parts are solving is that a car needs to store energy to make the wheels turn. Either way, you accomplish the task.

24:17Right. So it's less about the universal tools and more about universal problems that life solves in different ways. Certainly. With the minimal cell, the JCVI team had their hydrogen atom of biology. They were ready to uncover which genes were absolutely essential for life. Now, to our astonishment, one third of those genes, we didn't know what they did. A third of the minimal cell genome, so about 150 genes that were essential to life, were a mystery. John knew they were essential because without these genes, the cell would die. But the JCVI team just couldn't figure out what instructions these genes were giving to the cell.

25:12Today, about 10 years later, we know a little bit more. Only about 80 of these genes are unknown. But still, the minimal cell was supposed to clarify. Instead, it showed us how much more we had to learn. and these genes, there are similar genes in everything, in you and me, in the plants outside, in almost all bacteria, in yeast, in my dog here, everything. And so what that says is that after all we have learned about biology over the last hundred years, all that we've accomplished in medicine, a third of the essential genes for life. We don't know what they do. This really, really surprised us.

26:04We thought that we had a better understanding of this. Here you are with the minimal cell and there's still like a horizon to our understanding of biology that you couldn't see over. Yes, it really surprised me.

26:23It was one of the coolest discoveries of the century, in my opinion. Now we realize that a cell is even more complex than we initially thought when we started figuring it out. It just keeps getting more complex as we dig deeper into it. In 2017, Kate was gearing up to start her own synthetic biology lab. But she was thinking about a different scientific approach. I'm scared of cells. I don't believe that we'll ever be able to understand a complex living cell. So my approach is, I think, we can build ourselves a cell. Let's just build with that. If we can build a cell, we may be able to understand a cell.

27:06John and the JCVI team had always started with an already living cell and just kept it alive as they transplanted their lab-made DNA to give it instructions. But it would be something entirely different to spark life from its inanimate parts. In essence, not growing life, but building it. Making a membrane, taking all the goo and isolated parts of a cell, putting them together. And hope that it comes to life. John and others at JCVI, they gave us the goal. It told us, OK, this is the minimal set of functions that a cell needs to have. now go recreate it. For Kate, the minimal cell gave her the instruction manual, incomplete with some of those mystery genes, but still a list of the tasks that a cell needed to do in order to live.

28:00A list that she could use to build her own cell from scratch that could do those tasks. You know, if you talk to a normal biologist and say, I want to make life from scratch, they look at me like I grew a second head. But John was different. He's going to be angry that I said it, but he's the father. He's, he seriously, his vision pretty much started the field. He believed that it's possible to make a cell from scratch before anyone else thought that was cool or indeed possible. And he's been at it ever since. Building a cell from scratch, assembling it from pieces rather than growing it from another living cell would mean starting a whole new tree of life without this history of billions of years of evolution.

28:47I'm thinking of it more like making a molecular machine rather than making a living cell. A cell without mystery genes or unknown functions. A cell that's more understandable, more controllable, more capable of taking us into that sustainable future. I believe that synthetic biology is going to save the world. Maybe not me, but, you know, maybe Kate.