168. Chemistry, Evolved

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Use as directed.

Humility is not a word you often associate with prominent scientists, but for my guest today, Caltech Professor Frances Arnold, it was humility that led her to the research that would win a Nobel Prize in Chemistry.

So for at least a couple of years I was doing what all the other monkeys were doing.

And then I realized that's not going to work.

I'm not going to solve any interesting problems.

I just don't have a chance here.

So I had to think of something different.

Welcome to People I Mostly Admire with Steve Levitt.

While other scientists tried to manually manipulate the structure of enzymes to change the way they functioned, Frances Arnold decided to let nature do the heavy lifting for her, pioneering a process called directed evolution.

We'll get deep into that eventually, but I started our conversation with two very basic questions.

What even are enzymes and why are they important?

Everything in the biological world is made by these amazing molecular machines called enzymes.

They're just proteins, but these are magical proteins because they catalyze, they conduct the transformation of simple materials into really complex materials like trees or you or me.

Enzymes are the basis of the formation of life.

Now, what's strange is I'm an adult and I know a lot of things, but if you asked me to name enzymes, I know exactly two: amylase and lactase.

And that's partly because my dad was a gastroenterologist, so he talked about them all the time.

Given the importance of enzymes, do you have a sense of why they're almost invisible and unknown to regular people?

They're actually not as invisible invisible as you might seem to think.

Enzymes, for example, in your laundry detergents, take stains off of clothes.

They're even advertised on the bottles in some places.

They enable, under cold temperatures, to remove stains and reduce the energy costs of laundry immensely.

Enzymes are in your glucose diagnostic for diabetics.

Enzymes are responsible for turning grapes into wine.

Enzymes are responsible for making wonderful cheese.

You're right.

People don't give them the credit they deserve.

So let's talk about cytochrome P450BM3.

And I'm guessing very few of my listeners will have the foggiest idea what cytochrome P450BM3 is, but I know it occupies a very special place in your heart.

It definitely does.

The cytochrome P450s, a lot of people know what they are because those are the enzymes that are responsible for metabolizing or transforming drugs.

So your doctor will worry about drug interactions because they know that these enzymes are different in different people.

I got excited, not for those reasons, but for the magical, truly magical chemistry that the cytochrome P450 can do.

It can take molecular oxygen, just O2 from the air, and break it up and alter a chemical bond, like a carbon-hydrogen bond.

This enzyme can stick an oxygen in there and, for example, make your drug compound more soluble and excreted by your body.

That's incredible chemistry, to just use molecular oxygen and to insert that into a chemical at a very precise spot.

So I fell in love with these things for chemistry that no human being knew how to do.

Now, eventually, you're going to use that particular enzyme to demonstrate your breakthrough ideas on directed evolution that will win you the Nobel Prize many years later.

But were you already working with cytochrome P450 before you hit on the idea of directed evolution?

Nope.

P450s came later.

I started my early work on directed evolution using really boring enzymes.

Enzymes that hydrolyze chemical bonds.

So, for example, that break proteins down or break sugars down by inserting water into them.

That's called hydrolysis.

And chemists, oh my goodness, they're so bored by that chemistry because anything can hydrolyze these bonds.

So they pushed me to do really hard chemistry.

And of course, you would think about cytochrome P450s because to be able to put oxygen into a carbon-hydrogen bond, that's like methane to methanol, making fuels out of gas, all sorts of wonderful chemistry that no human being knew how to do.

So I grabbed the P450s and ran with them over 20 years after the first directed evolution experiments.

Okay, so going back to the beginning, it's the late 1980s, and there were many researchers who were interested in altering enzymes, and they were taking what's called a rational design approach.

Could you explain what that rational design approach is?

If you go back to the 1980s, protein engineering, that is modifying the sequence of amino acids that makes up a protein.

So making a new enzyme means you have to rewrite the sequence.

Nobody knew how to do that to make a better enzyme.

If you think about it, 1980s, this is pretty much the beginning of the DNA revolution.

Genentech's a startup company.

Amgen's a startup company.

We could cut and paste DNA, but we didn't know what to do with it.

It's like a composition.

We didn't know how to write it, to compose it.

But that didn't stop confident scientists from thinking they were going to do it, right?

There were a lot of people, you know, like the million monkeys at the keyboard trying to write Shakespeare.

That was kind of the nature of molecular engineering at the point, right?

No, that was what they said mine was.

They said I was the million monkeys.

But what they were trying to do, and it was a small field, the scientists were trying to uncover the structure of these amazing molecules for the first time.

And they felt that in order to engineer them, to rewrite their sequences and rewrite their functions, they'd actually have to go in and very fine-tune the changes, make very specific rational changes, which meant you had to get a structure first.

You had to have a really good understanding of the biochemistry and the mechanism.

You had to have a lot of knowledge that no one at the time really had.

And so it never worked.

Even to this day, right?

It still doesn't work very well.

It doesn't work at all.

The scientific publication means that you publish the positive results and the million negative results never get published.

So yes, you'll see papers where so-called rational design works, but the vast majority of experiments then and today lead to just garbage.

Aaron Powell, just to make clear, people understand why this rational design approach is so hard.

It starts with the fact that these enzymes are big and complicated.

I think I remember that the P450 enzyme has 400 amino acids strung together, and you've got 20 standard amino acids that come up all the time in...

the chemistry of life.

So like the number of possibilities, even if you understood how things work, the number of possible substitutions is essentially infinite.

And at that time, I don't think people really understood very much about protein folding.

Maybe you can explain it better than me.

Why can't people figure it out?

Oh, my goodness.

Proteins are incredibly beautiful and complicated.

To me, they're like a Beethoven symphony, intricate and held together by thousands of interactions that we just don't understand.

And to think that you could go in and fine-tune and manipulate the sequence so that you would catalyze a different chemical reaction or you'd have it catalyze a reaction on different materials, it's just too intricate.

And we didn't have enough understanding.

So even just getting the three-dimensional structure back in the 1980s and 1990s was an impossible problem for your P450.

That structure didn't become available till 20 years later.

You're in this world of scientists who are trying to tackle an impossible problem.

Do you remember the exact moment when the idea for directed evolution first came?

Do you, where you were, what you were doing?

I do remember because it came out of desperation.

I realized that my mind was not as big as everybody else's, that my understanding of biochemistry was limited.

I'm an engineer by training, not a biochemist.

And that I would have to do a thousand experiments to have the probability of having one positive result.

And I realized at that point, okay, let's just do random changes instead of me going in and making very specific modifications.

What if I just did a thousand experiments randomly and see what happens?

Let the enzyme tell me what matters.

Just at that time, this was the late 1980s, it became possible to do that.

The methods, the science of recombinant DNA, had moved ahead enough that we could start making a thousand things at once and test a thousand things at once.

Now, directed evolution is a bit more than that because it's not just making a lot of things and see what happens.

It's accumulating beneficial changes over multiple generations.

And that was really the trick, the difference between just random exploration and optimization by evolution.

And because I was trained as an engineer, I knew all about optimization problems.

And to me, evolution is the most beautiful of all the optimization algorithms.

And it works really well.

Just go out in nature and see.

Evolution is one of the most fantastic stories ever told.

And it's a process for engineering that works at all scales, from molecules all the way to ecosystems.

So to me, as an engineer, I said, oh my goodness, if I could use evolution to build new enzymes, I would have all the power of the biological world to work with.

A lot of the scientists I've talked to on this podcast, we've talked about their big ideas and often they didn't realize their big ideas were big when they first had them.

They'd say, oh, yeah, I had this idea, but I had this NSF grant that I had to finish off.

So it was two or three years before I actually started looking into the idea that in the end would be the one that changed the world.

For you, did a lot of time pass between this first kernel of the idea around evolution and when you got to work in the lab?

Or was it almost instantaneous?

It was almost instantaneous because I had had so many failures with the rational engineering approach that when I tried random changes and then accumulating those, it worked right away.

It worked in ways that no one could explain.

At the time, we didn't know why this beneficial mutation changed the property of the enzyme in this way.

But I had a process for engineering that gave me useful results.

And it did it in a way that no one could say, oh, I could have done that with one thousandth the experimental effort.

No one could do it.

And so I knew right away I had gold.

We'll be right back with more of my conversation with Nobel laureate Francis Arnold after this short break.

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So when I first heard about your directed evolution approach and I tried to imagine how you did it, I was really confused because I think while calling it directed evolution is simple and helps people understand it, what's different about what you're doing is, sure, I understand selective breeding of dogs, right?

It's completely obvious how we breed dogs or we breed cows to get characteristics we want.

But you are, quote, breeding enzymes, and enzymes are not living creatures.

This is a subtle distinction, but what you're doing is actually a much bigger breakthrough than I think people will give it credit for if you just call it evolution.

Do you know what I'm talking about?

You've created something that is in the spirit of evolution, but in which you as the researcher have to do a lot of extra steps that usually nature takes care of.

You're absolutely right.

That makes it more powerful, but also makes it a little bit harder, right?

If you're breeding dogs, your choice is who mates with whom and who goes on to parent the next generation in order to acquire the personality or the coat or whatever properties you want.

And I'll just point out, you are making non-natural things when you choose to do that.

I said, okay, I want to make highly non-natural enzymes.

Enzymes you couldn't go out to some distant jungle or to the the ocean and find your perfect enzyme.

I wanted to breed it in the laboratory.

And you're right.

I have to make a lot more choices then about what parents to use.

In fact, I have a lot more choices because you can mix monkeys and worms and you can have 33 parents and you can dial in any level of mutation that you want.

So the challenge was to figure out what is the process that's likely to give me a better protein, a better enzyme in a time scale of a PhD thesis or even a few months when I have all those choices to make.

It wasn't until I began to understand the process that I went, wow, my God, this is amazing.

So let's take some time and really have you talk about the process.

Even though I have a vague understanding of the big picture of what you do, it's still hard for me to imagine the specifics of how you pull it off.

The starting point must be a whole bunch of copies of the snippets of DNA that code for the enzyme you're interested in.

So let's just start at the very beginning.

Do you extract those snippets yourself in the lab or do you buy them from somebody else?

You can do it any way you like.

You can take an organism off the bottom of your shoe and extract its DNA.

You can buy it from a DNA supplier.

You can take it out of my freezer.

DNA is accessible now from all sorts of different sources.

So you start with the DNA that encodes a protein that is close to what you want, but doesn't have all the features.

And this is important.

You can't make something valuable out of nothing.

Evolution doesn't do that.

That's called creation.

Evolution means that you start with something and you optimize it.

Let's say you've got a cytochrome P450 BM3 that you've pulled from Bacillus megaterium.

I want to make it put oxygen on to the terminal position of ethane to make ethanol.

Ethane is a lot different from its natural reactant.

So I have to re-build that enzyme.

I have to artificially select for versions of that enzyme that will take ethane.

I start with a p450BM3 that has some of the catalytic machinery that I think I need for that, and I start mutating it and look at the progeny, the mutants, that have incipient capabilities.

So how do you do the mutation?

You've got all these snippets of DNA.

How do you mutate them?

Well, we can do it, right?

You go out and smoke some cigarettes and you might dial in some mutations.

For me, it's a lot easier because I've got these incredible reagents now that can copy DNA in the test tube.

And if you make those reagents a little bit sloppy, you add a little bit of ethanol to the mix, for example, so it just dials in a level of randomness to the copying, like you're making a Xerox over and over and over again, and you're getting fuzzier and fuzzier.

I can do that by the way that I copy the DNA.

Just to make sure I understand, so you have, say, a test tube that's full of these snippets of DNA, and then you dump in a reagent and some certain amount of ethanol.

You pour it in and you shake it, and that's your mutated DNA.

Yeah, pretty much.

Basically, what you're doing is you're copying it.

This was a Nobel Prize-winning invention, the polymerase chain reaction.

Carrie Mullis discovered that if you just copy DNA with a polymerase, you can make many copies of the DNA.

He was trying to make good copies.

I'm trying to make sloppy copies.

So we just do modifications to that method and make it really sloppy.

Okay, so you got all these mutated DNAs, but they can't survive on their own.

If you want them to grow and reproduce, you've got to put them inside of some kind of organism.

And how do you do that?

DNA is just the code.

So that's just the gene, and that's not going to reproduce.

You're right.

It's just a repository of the sequence.

So basically, what you do is you put the DNA inside of cells, and they start reading it as if it were their own DNA.

And from that, they translate it into proteins.

So through all those biology processes, they express the protein that's encoded by all those sloppy copies.

And this is a glorious thing about microbiology.

Each cell has a different gene sequence in it.

So all the DNAs go into cells, and each cell can be spread out on a plate.

So you take a toothpick, and you can pick individual bacterial colonies that have grown up on this plate.

And each one is expressing a different protein.

So you've got this test tube, and you've got all of these mutated DNAs.

They can't live on their own.

They need to be put into an organism, say into E.

coli or something.

Does a lab worker have to go and grab a snippet of DNA and drop them one by one into different E.

coli?

No, that's the great thing.

All this was invented 40, 50 years ago.

It's all the basis of recombinant DNA technology.

So you can take this laboratory manipulated DNA and just mix it with some beaten-up bacterial cells that have holes in their cell walls.

And it's easy to have reagents that do that.

And the DNA enters the cells, just goes in there.

And the cells, they don't know it's not their DNA.

They think it's their DNA and they start reading it.

So only one DNA manages to make it into each cell?

Yeah, on average you can do that.

There are little tricks that molecular biologists use to kill off the cells that don't have a new recombinant DNA in them.

You have an antibiotic resistance element, and you can kill off anything that doesn't have a new DNA.

And so now you have these bacterial cells that each have a new version of the DNA.

Then what you do is spread those out on a plate, and they grow into colonies, and then you pick each colony, put them into separate wells of a plate, and now you have a collection of cells that have the mutant DNA.

Okay, so you take these bacteria and you just spread them out on food, essentially things that bacteria like to eat, and then they grow like crazy.

They double every 20 minutes or something.

And they do it asexually, which is obviously really important because you need to reproduce identically, right?

You want millions of these bacteria that all carry the exact same DNA.

We don't know what gene is in what colony.

They're all different, more or less.

At this point, we really don't care.

What we care about at this point is: are they making a protein that's interesting?

So basically, we just collect the colonies, pick some cells from each colony, and put them in a plate where we can measure the new properties of the protein.

And now you've got all of these different candidates, which are potentially new enzyme creators.

Okay.

But somehow you got to figure out whether they're actually doing the job.

That's actually one of the tricky parts because it's not like natural selection where in evolution, the ones that grew would be the ones that have the survival benefit.

That's not what you've got.

You've got to go and somehow get the DNA out of this big mob of bacteria and figure out whether or not it's doing the job you want it to do.

And that doesn't seem obvious to me how to do that step.

It's like breeding cats and dogs.

You can look at the progeny and decide if you've been successful or not.

I do the same thing.

I look at these mutated enzymes and decide if I've been successful or not.

But each measurement is pretty detailed because my definition of successful might be, does it catalyze this new reaction?

And I have to have a way to measure that.

And in the first law of directed evolution, you get what you screen for.

So let's give you a real example.

When Procter and Gamble came to me in the very early days and asked me if I could make an enzyme that worked across all temperatures, so they could put one enzyme into their all-temperature cheer.

I said, yeah, I'll give you an enzyme that works across all temperatures, but it won't take stains off of clothes.

Because

I could measure how it hydrolyzed some peptide over different temperatures, but I had no way of measuring a thousand versions in laundry machines.

They said, okay, go ahead and do it anyway.

At the end of the experiment, we gave them enzymes that worked across all sorts of temperatures on compounds they weren't interested in.

But when you went and asked them, do they take stains off of clothes, you had to prey on that one.

Okay.

So in the typical experiment, how many different test tubes with different colonies at the first stage would you have?

1,000?

5,000?

We just use a 96-well tray that has essentially 96 little test tubes and a plate.

And we would look at maybe 10 of those, so 1,000 things.

And we could find beneficial mutations on a frequency of one in 300, 1 in 400.

But the most important thing, Steve, is evolution is not just random mutations.

It's the accumulation over multiple generations.

So we would have to do this over and over.

So typically out of 1,000, you might take three or four of those colonies and then you'd start the process over.

And you'd mutate those three three or four colonies, going back and mixing the ethanol and the reagents in with them, and just repeat this over and over.

Or we would recombine.

Sex is an important piece of the evolution.

Otherwise, you could ask, what are males there for, right?

If we could all carry the next generation, we'd have twice as many.

And so, what's the benefit of recombining your mutations with somebody else's?

And those benefits become really clear in the laboratory.

So we can recombine the three or four beneficial mutations

and then take that forward to the next generation.

I see, because you see hints that whatever you've changed on the DNA helps.

And so it makes sense that if you put together the changes on two or three that worked, that the cumulative effect of that is much more directed than the idea that, oh, let's just go back and jumble up this one that kind of worked in random ways.

That's interesting.

Yeah, you can use all the information.

And often, you're right, they accumulate in a beneficial way.

So we would often just throw all the beneficial mutations together and use that one that has all of them as the starting point for the next generation.

Or we would recombine randomly and see what combinations were best.

And how many rounds of these generations in a typical experiment do you go through?

10, 20, 100?

Well, back in the old days, we really could afford to do only three or four because I had to get the ideas published and every experiment was painful.

So we were gratified, this was the good luck, that really it only took three or four generations to make very significant changes in the properties of enzymes.

Now, as you describe this process, it sounds like there's as much art to it as science in the sense that all along the way, you've got to use intuition and make choices based on your gut about what to start with and what to recombine and how much ethanol to put in to make these mutations.

Is it your experience that some people just have a knack for getting good outcomes out of directed evolution and not because they necessarily have a lot of textbook knowledge of chemistry?

Well, some people are better than others, just like some breeders are better than others.

Also, your starting point is very important.

So people with great intuition can choose a starting point that's better.

People with more laboratory experience will be much cleaner in their measurements.

So yes, there is some art, but we're trying to remove some of that because it's an algorithmic process.

You should be able to even write an AI agent that can control the whole thing.

We're a ways away from doing that, but it's not out of the realm of possibility in the next few years that this whole thing will be automated and you can just press a button to make a new enzyme.

Now, I've heard that when you first began this work, other scientists were dismissive of the approach because it wasn't scientific enough.

Is that true?

Absolutely.

They felt that you should be able to use your big brain to figure out what changes would give rise to the new properties.

That making a thousand random mutations was what the monkeys would do, you know, the monkeys at the typewriter, that wouldn't be scientific.

But since I was an engineer and I knew this worked, I just said, okay, great.

I'm going to laugh all the way to the bank.

Was the bandwagon immediate?

Did people jump on right away or did it take a while?

So some people jumped on right away.

And those were the engineers.

Those were the people who actually wanted to make better enzymes.

All of industry immediately saw the value of this because they were really tired of waiting for all the work that they were supporting in rational design to work and they weren't getting much out of it.

So they jumped on to directed evolution immediately.

It took a lot longer for the greater scientific community to see the scientific benefit of using evolutions.

I imagine once you've designed this enzyme that you really want, you go back and you look at the structure and you can see what the mutations were.

And that must tell you so much about the chemistry that the rational design approach could only guess at.

It doesn't give all the answers because this so-called reverse engineering.

So you get the solution first, and then you've got three years left on your grant to figure out, all right, how did this happen?

And even if you have the mutations, so you know where the mutations are, because enzymes are so complicated, we often cannot fully understand how those mutations did it.

And that's the glory of biochemistry and enzymes, is that they're so complicated that even with the answers, we don't understand.

And that's why we don't understand all the products of natural evolution.

We have all those answers, but we haven't been able to reverse engineer them to truly understand.

What to me is so fascinating about this idea is that most breakthroughs take the form of we found some new compound or some new outcome.

But your breakthrough is really about a process, and it actually opens up the world to an infinite set of questions, which is now that I've got this process, what do I apply it to?

I know there's so many success stories.

Could you just run through a couple of the success stories in some detail of directed evolution?

Oh, I have so many enzymes that I truly love.

But one story is biofuels.

A lot of interest in making sustainable aviation fuel, for example, from waste products of biomass.

There's lots of agricultural waste products that are just now being burned or grounded into the ground.

If you could convert those sugars that are present in that biomass, which ultimately comes from sunlight and carbon dioxide, so you're not pumping oil out of the ground, you're actually taking CO2 out of the atmosphere and turning it into biofuels.

Right now, we can turn sugars into ethanol.

Humans have been doing that for thousands of years.

But we argued, okay, let's turn it into isobutanol.

And that's a four-carbon alcohol that's a great precursor to a jet fuel.

We engineered a yeast that had different enzymes in it, but in the metabolism, it had one enzyme that was using the wrong, we call it a cofactor.

It was a metabolic reagent inside the cell that it really needed to be switched.

So, this is an existing yeast.

There's some yeast out there, and this yeast is eating corn husks or something like that.

Yeah, the yeasts can break down the sugars and convert them to ethanol.

But you didn't want ethanol, you wanted something much more complicated.

Yeah, we wanted isobutanol.

And you could see that the yeast just needed a little tweak.

So, it needed a couple of bigger tweaks to make the precursor to jet fuel, but it needed a very fine tweak in its ability to use a particular reagent inside of its cells.

And we needed to alter that specificity so that it would be really efficient.

I mean, if you're going to make jet fuel, you have to do it very efficiently to compete with pumping oil out of the ground because that's cheap.

So we had to make this yeast really, really good at making isobutanol.

So we evolved one of the enzymes to switch its specificity for this cofactor.

We had no idea how to do that, but by directed evolution, we started learning what the rules are.

We made the enzyme, and in fact, the whole company was founded based on this technology.

But the great thing is, and this goes back to your earlier question about what do you learn from it, we could reverse engineer the solutions that we got out of these experiments to come up with a recipe, a general recipe that others could use to go in and change that specificity for the cofactor on any other enzyme.

Aaron Powell,

you've talked about how cheap oil is, which is really true.

Oil is really, really cheap.

How is the commercial success?

You said you founded a company.

Have you been able to compete in the long run with oil?

Back in 2005, when we started the company to make jet fuel, the price of oil was $150 a barrel.

This was the big spike in oil prices.

And corn was cheap.

So we said, okay, we can convert corn into isobutanol and make the product less expensive than if you get it from oil.

So we started the company and it went public and everybody was super excited.

And then what happened?

Fracking comes along.

And fracking.

dramatically increased the supply in the United States and dramatically reduced oil prices.

And at the same time, the price of corn went up.

So now you can't make any money converting corn into fuel.

And I've watched over my career these price fluctuations in 10, 20 year cycles.

It will go back.

We will see the price of oil go up again, but who knows when that will be?

Maybe when we realize that putting carbon dioxide into the atmosphere is bad.

Aaron Powell, so this company that's making the biofuels, it's still around.

How is it trying to cope with the fact that the price of oil is so low?

Aaron Powell, it makes ethanol.

They're still in business.

We still have a nice plant in Minnesota.

But the technology is there if it ever becomes useful.

You have another company you launched called Provivi, and I found the goal of that company to be absolutely fascinating.

You're trying to control insect populations in ways other than using toxic insecticides.

Could you talk about the science underlying that approach?

Oh, that's such a wonderful idea.

I wish I had thought of it.

My former PhD student, Pedro Coelho, worked with another former PhD student, Peter Meinhold, to found Provivi, where they would interfere with insect sex.

So the whole goal is to get rid of pesticides because pesticides are so toxic.

They're killing insect populations well beyond the target pests.

The residues show up in your food and everywhere.

So we wanted to use an old idea.

So you've got this moth that has a caterpillar that just devastates crops.

The male comes in and fertilizes her.

So imagine this.

She's got a Chanel number five that she emits.

And that's how the male can find her and have sex.

So if you just go around and spray the whole field with Chanel number five, suddenly he's confused and he can't find her because she's everywhere.

Nothing toxic about it.

You don't kill anybody.

The problem is that her Chanel number five is such an intricate structure that it's really, really expensive to chemically synthesize.

And humans had only chemically synthesized the mating pheromones of a few pests that are known in extremely expensive crops like stone fruits and various nuts, grapes sometimes.

But they couldn't couldn't do it for rice or corn or soybeans, the things that feed people everywhere and for which the pesticides are being laid out in billions of pounds.

So we took it upon ourselves to develop new methods, biological methods, as well as new chemical methods to synthesize these at one-tenth the cost of the normal chemical synthesis.

So we talked about P450 as a starting point when you want to do the enzyme stuff.

What do you start with for pheromones?

Pheromones, because they're a natural product, they're made by insects, there's enzymes in the insects that already make them.

And so you could start, for example, with the natural biological pathways that do that.

And you could take the insect pathways and put them in a yeast, for example.

And then some of the enzymes can be optimized by directed evolution.

And is this still hypothetical, or is Pro-V actually churning out these pheromones that are having real world impacts, protecting crops?

Provivi is making tons, literal ton quantities of pheromones for corn, for soybeans, and rice all over the world.

I suppose the problem is the same as you have with oil, is that insecticides are probably relatively cheap.

Are you able to compete on price with the mass insecticides?

It's a tough, tough business.

First of all, it's a new idea, and farmers are extremely conservative.

These farmers, their whole livelihoods depend each year on success.

So it's hard for them to do experiments.

It's a tough market to be in.

That said, we're still surviving and providing these in various parts of the world.

We've been talking about very practical commercial applications, but back in your Caltech lab, you've also been doing wild stuff that at least to me sounds more like science fiction than actual science.

Biochemists only study the chemistry that nature has.

But there's a whole universe of chemistry that no one has ever invented, where now you could imagine evolving enzymes to go.

So we've been exploring that whole new space of non-natural chemistry.

The space of non-natural chemistry is way bigger than the universe of nature's chemistry.

So one great example that we did, oh, almost 10 years ago now, is making carbon-silicon bonds.

Half the world has wondered, or at least half the nerd world, which is the world I hang out in, why not silicon-based life?

Why does nature not incorporate silicon into living systems?

We're made of carbon, oxygen, nitrogen, a little bit of phosphorus, a couple metals.

But you never see silicon in there, even though silicon is the second most abundant element on the Earth's crust after oxygen.

And there's no enzymes that have ever been shown to forge carbon-silicon bonds.

So we said, okay,

could you imagine a future where an enzyme that forges carbon-silicon bonds could pop up?

So we did that experiment.

We created an environment where that would be possible.

And we took a bunch of iron proteins, iron-containing proteins, and just asked them, can you do this?

And sure enough, there are millions of iron-containing proteins out there on the planet that can form carbon-silicon bonds.

In other words, that function is already out there in the natural world.

It's just nature hasn't utilized it.

So then we asked, would that evolve?

Could you make it better and better, mimicking natural selection?

The answer to that was yes.

We took a little protein that had iron in it and made this carbon-silicon bond.

And over three generations, we made something that was much better at making the carbon-silicon bond than a human had ever done.

And I should point out, humans have been doing this chemistry for a long time because we make silicones and caulks and sealants and paints and hair gels and deodorants that have siloxanes in them.

But we showed that an enzyme could forge these carbon-silicon bonds as well, and that it could evolve.

It sounds to me, in some sense, like you think this new to nature research that you're doing now, do you think that's what people in 100 years are going to look back and say Francis Arnold changed everything?

Oh, I don't know whether I can take credit for that, but I will say it's a very rapidly growing field.

I think it's inspired chemists, so young chemists who are looking, how can I make an impact in the field of chemistry?

They realize that genetically encoded chemistry is a completely unexplored space, full of gold pieces for them to discover.

The field already in 10 years has exploded.

We did some of the first experiments and maybe kick-started the field a bit, but what people have done since our work is really mind-boggling.

If you look forward 50 or 100 years, what kind of problems do you expect this approach will solve for us?

So, if you can genetically encode, that is, find a sequence of DNA that encodes a catalyst for any chemical reaction, that means you could get microbes to replace all chemists.

Then, we could do it cleanly and efficiently with few waste products and recycle everything and build materials based from carbon dioxide and sunlight, just like nature does.

Wouldn't that be incredible?

We could make anything.

You're listening to People I Mostly Admire.

I'm Steve Levitt.

And after this short break, Nobel laureate Frances Arnold and I will return to talk about how she barely finished high school.

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As you're listening to this conversation, you're probably assuming that in high school, Frances was a straight-A student, science club geek, and the apple of her parents' eyes.

But as is so often the case with my guests, even ones who have won a Nobel Prize, Frances was a lost kid who had no idea what she wanted to do with her life.

I was a 15-year-old in Pittsburgh.

Pittsburgh was a decaying industrial city.

This was 1971.

It was the height of of the Vietnam War.

We didn't trust our parents.

There was no future.

There was no trust.

And I was a major rebel at that time.

I decided that I was going to go out and make my own world,

which meant hitchhiking to Vietnam War protests, having my own apartment, barely ever going to school.

But by golly, I was going to do it my way.

Literally, you moved out of your home at the age age of 15.

Did you just announce one day to your parents that you were going to live somewhere else?

Pretty much.

I had four brothers, and things were pretty strict around my household, and I was considered a bad influence on my brothers.

And so, how did you support yourself at the age of 15?

You had to support yourself, right?

I did.

I had to pay rent on a horrible apartment.

And how did you do that?

I worked in pizza parlors.

When I turned 17, nobody ever looked at driver's licenses back then.

So, I said I was 22, and I got a really good job as a cocktail waitress.

I drove a taxi, Yellow Cab Company of Pittsburgh.

I worked in department stores all through high school.

And I did manage to graduate thanks to the intervention of the principal who, after I got into Princeton, decided he would allow me to graduate.

How did you get into Princeton?

That makes no sense.

I did really well on the SATs, and I had won some state prizes for art.

Plus, I wrote a really convincing essay.

Do you remember what your essay was about?

It was all about my life.

But also, and I have to admit this, my father was a PhD from Princeton and knew the Dean of Engineering.

So that probably helped too.

My father said, Francis, no one will ever marry you.

So you're going to need to have a job.

And if you want to have a job, be an engineer.

So I took his advice.

Wait, why did you take your father's advice?

You were really.

Yeah, I know, but by 17, I really wanted to get out of the dirty, lousy apartments.

I didn't like high school, but I thought college would be better because I wasn't living with my parents.

And so I took his advice and I graduated with a degree in mechanical and aerospace engineering.

It sounds like you had a lot of fun and a lot of adventure.

And those adventures actually shaped who you eventually came to be.

In contrast, when I look at young people today, I feel like they're in a big hurry.

The high school and college-age kids that I'm around live with this belief that if they step off the most direct path to some goal for a week, for an hour, they'll be ruined.

But your story is a great reminder of how stepping off the path doesn't ruin you.

In fact, in many ways, it caused you to flourish.

Do you have that same sense that something's changed and everyone's afraid to take a little gamble here and there?

Steve, I think you're absolutely right.

I often talk to young people and encourage them to try things, to try something different.

This is a motto in my household.

Don't do what all the other monkeys are doing.

If you try things, you don't have to continue to do them if you don't like them, but you'll never know if you don't try it.

So take a different path and collect experiences as if they're money in the bank.

Even if it's a bad experience, it will teach you something about who you are and what you care about.

I decided I would become a professor when I was 29, and I'd had many other jobs that I didn't like before that, but that prepared me to put knowledge together in a different way.

It prepared me to appreciate a really good situation when I finally did find it.

And it prepared me to be resilient in the face of adversity.

Trevor Burrus, Jr.: I put the blame on young people.

As I just described it, I said, look, they're all uptight and they won't take any risks.

But obviously, a lot of the blame has to go on to people in our generation.

A good example is you've won a Nobel Prize in Chemistry, and yet you say that freshman chemistry is a terrible course.

That's got to be on us, right?

There must be a way that we can create an environment that would allow kids to thrive in a way that we haven't succeeded in doing.

So I think some blame goes on the teachers and the way that courses are taught.

But also it's just the way that you get into what you love.

I think I got a D in chemistry when I was at Princeton and I wasn't at all interested in it, so I didn't spend any time with it.

But then when I was a graduate student and I loved enzymes, chemistry suddenly became fascinating.

So it was the context.

And we don't give young people enough context for them to become fascinated about getting into the nitty-gritty.

Chemistry is full of nitty-gritty stuff that you really just need to know, as is engineering.

But if you don't have the context, it's just work.

And who wants to do just work?

Who wants to do just work?

The guests I have in this show differ from one another in so many ways, but one trait they mostly share is that they love what they do.

If you can find something that you love and someone is willing to pay you to do it, I call that success.

If you happen also to win a Nobel Prize along the way, well, that's the icing on the cake.

This is a point in the show where I invite my producer, Morganon, to take a listener question.

Hi, Steve.

Instead of a listener question today, I would like an update on the Levitt Lab High School.

You have launched a radical new high school on the Arizona State University campus.

We've talked about this in the past on the show, but in the months since we've talked about it, the school has actually opened.

Can you give me an update on what's going on?

I sure can.

And I'm glad you brought that up, Morgan, because I love what we're doing at the school.

It's not a big school yet.

Just got 50 kids.

But our goal with the school is to try to make this school a place where kids actually want to be and at the same time, have them learn two to three times as much as they would in a traditional school.

So Steve, it seems like it would be possible to accomplish one of those goals.

How's it going on trying to accomplish both of those goals?

It sounds like those two would be in conflict, Morgan, but what I'm seeing so far is that actually by making a school a place where kids want to be, it makes it so much easier to try to get them to learn.

Much of the philosophy that we're pushing here, it fits in perfectly with the episode we did with David Yeager.

If you remember, he was from the University of Texas at Austin, and he talked about a different way of interacting with young people, in which you have both high expectations and high support.

And that's really the model of our school.

We have adults there who clearly care about the kids, and the kids can see that.

We give the kids a lot of autonomy about what they're studying and when they study, and they are incredibly engaged.

Can you give me a little flavor of what their day is like?

Yeah, one little thing is we start the day later.

Kids don't like to get up early in the morning, so we start the day at 9, and it just allows them to ease into the day.

We have almost no traditional classes.

They're doing a lot of individualized work, and so there's a lot of unstructured time.

We do have some structured class time, so we have things called wonder sessions.

They're mostly science-based, and we just try to deliver to them a really interesting puzzle and then solve it in real time with the kids all working together to try to figure it out.

And another organized event that they have is something we call seminar.

And that's where the kids take a complicated topic like, is immigration good or bad?

And we deliver them a bunch of data.

So they see a bunch of tables and figures to get some of the basic facts.

And then we give them readings from people who are sensible and thoughtful, who are in favor of immigration.

And we give them readings from people who are sensible and thoughtful and are against immigration.

It isn't a debate.

It's just trying to think thoughtfully and slowly and carefully about hard problems with the insight that people can disagree and still be reasonable people and that they have to make up their own minds on these tough issues.

The kids spend a lot of their time on deep dive projects of the kids' own inventions focused on topics they care about and the ideas that they are going to do a bunch of research and then create something with their hands, an actual physical object or a video of some kind that will be a real deliverable at the end of the day, as opposed to the way you show mastery is by taking an exam.

We just try to have as few exams as possible.

I spent the day there last week and the kids were so excited.

At the end of the day, they stand around a circle and they talk about how they feel and the kids were saying things like, I love coming to school in the morning and I hate going home at the end of the day.

And honestly, kid after kid said these things and it just brings tears to my eyes.

And it was actually really funny because I was talking to the parents afterwards.

And one of the parents said to me, wait, you're saying it brings tears to your eyes, but in the episode with Steve Pinker on Pima, you said that you don't cry ever.

There's something so inspirational about creating an environment where the kids seem so at home.

And I have deep confidence that they're really learning a lot.

Steve, what does it cost to go to the school and what does it cost to teach these kids?

Well, it costs nothing to go to the school.

It is a public charter school, so it's free to any and all students.

In terms of our costs, we think at scale we can do this for about $15,000 per student, which is on par or less than what it costs to give a public school education in almost every district in the country.

Oh my god.

It's not very resource intensive.

What we've managed to do is take a lot of the tests that chew up the time of a typical teacher and we've centralized all of that.

And so really we don't have to have that many teachers on the ground because they spend all their time trying to connect with students and move obstacles out of the students way.

And they don't spend all that time on tests, which really are easy to centralize.

So what are your future plans for the school?

We are hoping to expand our current location.

And next year, it looks like we might be on track to open new schools in the Boston area.

Oh, wow.

And in Los Angeles, and maybe one more in Arizona.

So we're keeping busy.

We feel like we're really on to something great.

And we want to get this out to as many kids as possible.

Listeners, if you want to learn more about the Levitt Lab High School on the campus of Arizona State University, the website is thelevittlab.com.

If you have a question for Steve Levitt or a problem that could use an economic solution, our email address is pima at freakonomics.com.

That's P-I-M-A at freakonomics.com.

We read every email that's sent, and we look forward to reading yours.

Next week, we've got an encore presentation of a conversation I had with Moon Duchin.

She's a mathematician who studies gerrymandering.

It's a topic that has never been as relevant as it is today.

And in two weeks, we'll be back with a brand new episode featuring Irving Finkel.

He's a leading expert on cuneiform, the ancient writing system from Mesopotamia.

It's a subject I know almost nothing about, and I am very excited to learn more.

People look at you rather weirdly if you say you're a specialist in cuneiform writing because they say, well, what use can that be?

As always, thanks for listening and we'll see you back soon.

People I Mostly Admire is part of the Freakonomics Radio Network, which also includes Freakonomics Radio and the Economics of Everyday Things.

All our shows are produced by Stitcher and Renbud Radio.

This episode was produced by Morgan Levy and mixed by Jasmine Klinger and Greg Ripon.

We had research assistance from Daniel Moritz-Rapson.

Our theme music was composed by Luis Guerra.

We can be reached at pima at freakonomics.com.

That's P-I-M-A at freakonomics.com.

Thanks for listening.

So that is what we call a Darwin Award, where you remove yourself from the gene pool by doing something really dumb.

You almost won a Darwin Award.

The Freakonomics Radio Network, the hidden side of everything.

Stitcher.

Hey, everybody, it's Babs.

You know, one thing that makes the holiday season so magical is the traditions we share year after year.

And that's why I'm so excited to tell you about Birch Lane.

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Hi, I'm Angie Hicks, co-founder of Angie.

And one thing I've learned is that you buy a house, but you make it a home.

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