Pushkin. There's this problem that's been going on in the background in the United States for a long time. The problem is this, there are not enough drugs to go around. This, strangely, is not about expensive new drugs that people can't afford. This is about old, cheap generic drugs, drugs that just are not available in sufficient quantities at any price. A national pharmacist group recently reported shortages of three hundred and
nine of these generic drugs. There are multiple causes. It could be the bankruptcy of some little known generic drug maker. Could be a sudden surge in demand. Could be the failure of some distant crop that is the source of an essential drug ingredient. It's a complicated problem built out of lots of little problems. But broadly speaking, the supply chain for generic drugs is long and opaque and exists largely outside of the United States, so it is very
difficult to see these drug shortages coming. I'm Jacob Goldstein and this is What's Your Problem, the show where I talk to people who are trying to make technological progress. My guest today is Christina Smolky. She's a professor at Stanford and the co founder and CEO of a company called Anthea. It's a synthetic biology company. They're in the business of genetically engineering microorganisms to produce commercial products. Christina's problem is this, how do you turn ye cells into
tiny factories to create the active ingredients in drugs. If Christina and her colleagues solve this problem, they won't solve the drug shortage problem entirely, but they might help make it better.
I actually started not in industry, not as a CEO of a company, but I started as a professor. And so there, you know, I was coming out the field in a more academic way, looking at here's the state of the technology, but think about how much more we could do if we really open this up. And so, you know, it was really let's focus on the hard problems. Let's focus on the problems that people say right now are impossible, that you will never get this to work,
the science just can't do it. And let's figure out can we actually you know, make these impossible solutions possible to really address these problems. And so that's where it started. You know, for about fifteen years of my career was really focusing on the you know, foundational scientific breakthroughs that were needed to build a company like Anthea and really bring those transformations into the industry.
So when you when you're starting out, you're thinking, Okay, there is this nascent field synthetic biology, this basic idea, I want to advance this field to the point where we can make you know, drugs or the active ingredient in drugs exactly what are the things people didn't know how to do that you and your colleagues had to figure out.
So there was a lot to figure out. And you know, first and foremost when you looked at where the field was when we when I started in this space, most of where everybody focused and it's actually true still today is on engineering cells to produce relatively simple compounds. So let's just take a step back, and you know, we use yeast, very similar organism that yeah, basically identical organism that we've been using for centuries to brew beer, ferment wine, right,
so we have a long standing history of that. That's biomanufacturing. But what the yeast of producing is ethanol, right, carbon dioxide, very simple molecules that it does naturally. Now take a step back, we want that yeast to produce a very complex chemotherapeutic, right, or a very complex anti infective. How
do we teach it to do that? And when you looked at where we started, you know, in this in this field, what the field was capable of doing was basically taking a organism like yeast and maybe moving you know, three genes or three proteins into that organism. That basically allowed the industry to produce very simple compounds.
Perfume, right. I feel like perfume was one of the big ones, sense exactly.
Very close in structure to what the yeast could already make. Right, in order to actually make these you know, drug ingredients, we had to be able to transform the field from thinking about and being able to sort of routinely move maybe three to six genes or protein coding sequences into the cell to be able to actually move twenty thirty
or more genes and protein sequences into a cell. And again, these drug ingredients that we rely on are so you know, they're so different, and they're so complicated from what yeast would normally make.
Yes, it was not built to make chemotherapy drugs, right, to spend a billion years evolving to make the drugs we need to cure cancer exactly. So it is the basic problem that like if you try and swap in that many genes at once, the cell will just kind of blow up and die. Be like, what are you doing to me? I mean it's that the basic starting problem.
Yeah, you know that was certainly I would say the general sort of I guess thinking at the time, right, And you know, when we propose to do this, you know, in my academic lab, we had a difficult time getting funding for it, even at like a research level, because the reviews would come back and say, this is you know, this is impossible. There's no reason to even try to do this because it will never work.
It's an engineering problem at a certain level at that point, right, That is the sort of you have if you have the genomic information, you know what genes you want, but you got to figure out how to make them work in a yeast, right, And I mean I want to ask how do you do that? Although I know that's like a ten year long answer, So maybe what I'll ask instead is like, is there one piece of figuring
out how to do that that you can explain? You know, is there one one thing you had to figure out along the way where you came upon it and it didn't work, and you figured out how to make it work.
Yeah, and you're right, this is an engineering problem. It's a systems engineering problem. Right. So ultimately we're asking the yeast to be this sort of mini nanofactory to produce drug ingredients. Right, So not these sort of macro factories we build out, you know, in our world, but really kind of a cellular factory. So what's happening inside the cell.
One of the things that we brought to this field is sort of a very unique strategy was to say, you know, let's not the cell is not just a bag, right where everything just sort of happens in this nebulous form. Let's really think smartly about the cell as a system and the biochemical environments that are in different locations of
the cell. And then when we change the sequence of the proteins, we would very specifically give the yeast directions of make this particular protein in this part of the cell because there's a particular pH to do some environment, you know. And then but this other part of you know, the molecular machinery, the other steps of the proteins, we want you to actually make it in this other area of the cell.
So just to write to pick up on your factory metaphors. So it's like the naive way to think about the inside of the cell is just like a big empty room. But you're thinking, like, no, it's not like that. I mean, if the factory is the analogy, it's like, this part over here is like where we should be whatever putting the wheels on, and this part over here is clearly where like the robot arms should be bolting the chassis together.
Because different parts of the inside of the cell are different, are biochemically different, and some parts will work to do some things and other parts will work to do other things, and you can't do it in the wrong place or it won't work exactly exactly.
I mean, that's an exact metaphor, right, and the exact way to think about it, right.
And so let me ask just a few dumb questions about that, because it's interesting. How do you tell the cell where to do it?
It ultimately comes down to the directions you put in the DNA, right, And it comes back to that gencoding sequence where I mean, again it's biology does remarkable things, but within you know, within that encoded sequence, you know there are directions of you know, again exactly what amino acids. You know, how you are basically making that protein amino
acid by amino acid. But there are also directions that basically tell a cell and the cell's native machinery, no, you're going to actually make the protein over in this location right now. We want you to transport it over there. We want you to move this over here, We want
you to insert it into this membrane. So you know, I mean again, the cell is, it's so sophisticated, right, we just you know, we just have to basically be able to understand enough about the directions that the cell uses and reads in its own native processes so that we can begin to leverage you know, the strategies and the routes that it has you know, developed, is a way to move proteins to particular locations and cells.
So you figure that out over some period of time. Is there a first drug ingredient that you get a Y cell to make? Is there some like proof of concept moment?
Yeah? There, yes, there was. So the drug ingredient that we initially demonstrated with this is an ingredient called the dane And this is actually an ingredient that is extracted from medicinal plants, and it's an ingredient that's used to produce about half a dozen different drug ingredients, from drugs that are used to treat you very severe pain, to drugs that are used as rescue mediations to treat addiction and as well as overdose.
Like the drug that has the brand name Narcan. Is it not lots like that?
Oh?
Interesting?
Is that drug Narcan and naloxone is a drug that is used that is basically produced from the vein. We published that demonstration, that proof of principal demonstration in twenty fifteen, so that was and again that was done prior to us starting anthea. It was done in our the academic lab at Stanford, and again that particular demonstration, it took
over a decade, right to bring it all together. So it was a very long term project in my lab for the very reasons that we discussed for all of these challenges, right, and it was one that because I would say the field in general viewed it to be impossible and thus not worth you know, spending research dollars on. It was one that we spent a lot of time bootstrapping in my lab because I really had a lot of conviction that we could get this done.
So you publish this paper to show that you can get yeased to produce this drug ingredient. What happens next?
The next questions are can it be done at an efficiency and scale such that this can really offer you know, solutions right to the industry, Because if you take what we showed in twenty fifteen tried to scale it up, I mean you would it would not be offering a solution because it was so inefficient. Is still not efficiently converting the sugar to that drug ingredient such that it would just be too expensive because ultimately price is a
big consideration. So you know, there were and just to give you like a sense of the degree what we're discussing here, right again, when we look at what was demonstrated in twenty fifteen, you know the yest we're producing very low concentrations of that drug ingredient. We at Inthea had to optimize that by over a millionfold, and not
just in scale but in efficiency of converting. That had to be able to produce a million times higher concentration of that drug ingredient than what we demonstrated.
A million times more drug per unit.
Sugar exactly right, or per unit use really right, So.
The yeast has to get way, way way better. Sure it can make the drug. It's really bad at making the drug. In two, it's terrible at making it exactly.
That's sort of independent of scale, you know, in terms of like the volume that you're producing. It's saying, okay, you know, whether you're we're growing you at a mill or we're growing you at you know, one hundred thousand liters, we need you to really steff up your game.
And yeah, right, you.
Know, converting that sugar into the drug product. And so again that comes back to a lot it's an engineering problem.
So okay, this is the next problem you have what you know, what what are some of the things you do to increase efficiency.
So you know, again if we come back to this idea of you know, you're assembling a car and a factory, right and it's going through these different lines to sort of build it in a modular way. That's you know, the sort of manufacturing assembly line that you've developed is sort of where you want your your drug ingredient to stay on track, right, But it is operating within this
more broader complex system of the yeast. And so the yeast will have just natural processes that it's developed, and some of those will actually begin to interface with the assembly line that you've put in, and so it.
Can start the yeast is busy being a yeast cell, right, Like the yeast was not born to make this drug ingredient.
And it's you know, it's busy, as you say, being in a e cell. It has its own objectives that it wants to achieve, right in terms of you know, growing, you know, doubling, and you know, producing its own products. Yeah, it has its own dreams and you know, things that it wants to accomplish. And so it's you know, the natural system that you put it within is basically interfacing
with that assembly line that you've put it in. And in many cases, right those natural systems can actually pull away or divert your drug ingredient from the desired endpoint, just you know, because of these interactions.
That's the weird thing, Like the yeast is making you crazy, but like the yeast is also like the thing that's making the thing you need exactly right, and so you have.
To really balance that very carefully because and so I mean, you want the use to be multiplying, because every time it multiplies, it's providing another cell factory that's going to
reduce drug ingredients. So you it's this balance between allowing the EAST to obtain its objectives, which also feed into your objectives, but then where it is, you know, being disruptive to your process, trying to make surgical changes that will still allow the yeast to be relatively happy, you know, and feel like it is doing what it needs to do, but still but then allowing more of your drug ingredient to grow, to go towards the product that you ultimately want to produce.
A few weeks ago and they announced that they had completed their first manufacturing scale production of the bay and they plan to start selling the ingredient to drug makers next year. We'll be back in a minute. Now, back to the show. So let's talk about drug shortages. To me, still somewhat strange phenomenon in the United States, a country where we're a rich country and we spend tons of money on drugs, although no generic drugs are cheap, and
that's part of the thing. We can talk about that, but it is remarkable how widespread and persistent drug shortages are shortages in particular of generic drugs, and they seem to be increasing over the last few years. What's going on there?
I mean, I think one thing that has been noted and that is notable is that in the US we do not have manufacturing capacity to produce drug ingredients or drug products really, right, It's very limited. Most of the drugs that we consume are basically produced outside of the US about ninety percent. What that ultimately plays into quite a bit is lack of transparency and control over these supply chains, right, because we don't have any domestic capacity.
Because the supply chains actually are quite complex in terms of the different players involved, oftentimes we don't have a lot of notice or yeah, really notice or transparency into if we expect that there's going to be an issue with the supply chain. Right, there's just again very limited transparency.
It's very difficult to track through all the supply chains. Now, when you talk about just manufacturing technology for drugs and the ways that they're being manufactured, there's essentially two different ways that all of our drugs are being produced. Right. We talked about agricultural sourcing, which a lot of that is sort of where we focus. But again about forty percent of our drugs are being produced through agricultural sourcing.
These are very complex basically drug ingredients. We cannot produce them at scale with chemical synthesis, and so we still basically rely on biological synthesis to produce them.
To be clear, you mean they come from plants.
Plants, sometimes other animals, right, So you know there are in drug ingredients that are a extracted from animals or even you know, sometimes it could be rare marine coral. I mean, you know, but so you do really get a spectrum. I think the bulk of it is going to be plants, but it will meld into other areas. But all of these you can imagine, these supply chains
are increasingly vulnerable. If you're farming in a small number of areas across the globe and you have a fire that goes through a region, or a flood, or you know, any one of the sort of climate catastrophes we're sort of seen and out of increasing frequency that can really wipe out basically the crops and a large fraction of
the material that's being produced in any given year. And so there can have these variabilities, right, also variabilities in farming practices, variability and pest and disease that go through an area. The point is that there's a lot of vulnerability and variability that is becoming increasingly difficult to predict and also just increasing in frequency. So what that means is that supplies can vary right from year to year,
from growing season to growing season. And the other thing is because the manufacturing cycles are so long, you know, any one of these because of the time it takes to grow the biomass or the organism right to complete a manufacturing cycle. For most medicinal plants, it can be two years to sometimes five years, right, just because of
how slow they might grow. So if you wipe out a crop for any given growing season, you don't have the ability to just grow more, right, you have to replant, receive That can take years, So there's no ability to sort of respond rapidly if demand changes or if you know, part of your supply chain basically goes down with fermentation. Right now, what you have is very sort of consistent infrastructure.
It's basically a fermentation vat whether you're producing a chemotherapeutic, a sedative and anti infective right, or a pain medication. Regardless of what ingredient you're producing, the infrastructure is the same. You're basically swapping in different strains of yeast, and the manufacturing cycle time is so fast, right, It's basically two weeks a week to grow the yeast, get the drug produced, and then an other several days to purify it to
really pure form. So because of the fast manufacturing cycle time, and then because the infrastructure is very readily repurposable, right, because ultimately it's the same, you can and you can actually switch a facility from producing a chemotherapeutic to producing a sedative in a matter of two days.
So the dream is to be the swing supply or for whatever ingredient is in short supply in a way that people who are using traditional technologies cannot be because of the nature of the technology.
Yeah, I mean, I would let me just say, I think I think for for me, the dream is actually to disrupt the market, right, I mean, we shouldn't be farming drug ingredients. It's very wasteful from a resource perspective that land can be used to produce food, right, and other products that you know we need for a growing population, right, you waste a lot of biomass. You waste a lot of water, I mean other things because most of that plant material you're basically throwing away. It's just not a
good use of resources. So really the dream is this techno should disrupt and transform the industry. It just makes more sense, right. It can actually provide these ingredients at a cheaper cost, It could provide them at a more consistent, better quality, right, And it's it's just a more efficient use of resources. So it really should be that transformation in the industry.
We'll be back in a minute with the lightning round. Back to the show. We just have to do a lightning round, and then you can go. As a professor of bioengineering, what do you understand about biology and or engineering that most people don't understand?
I think you know. One thing is as engineers, we provide solutions. We develop solutions with imperfect data, right, and imperfect knowledge of the system. We have to have enough knowledge and enough day to provide solutions that are going
to be meaningful, that are going to scale, right. But and I think that can be at odds with a biologist, right, or someone who's studying the pure science where we really want to understand all the nuance, you know, understand everything in sort of the beautiful detailed intricacy.
What's your favorite yeast?
Yeah, I really do like sacrimicos seravisier and you.
Know, tell me about sacrimisis.
Well, it's a it's a strain of use that we use at anthea, but it's also the strain of right, it's also use that are used again as brewers use you know Baker's uast.
Right, if you weren't working on drug ingredients, what would you be working on?
It's a good question. There's there's different ways to take that. I mean, I think that there are a lot of problems that are important in the context of synthetic biology. You know, I could also I would love to also there's another part of my life and sort of a second life that I might live where I'm in a very different industry. Right, So you know, but that that did not that is not the road that we took.
What like, I feel like there's a very particular thing in your mind as you say that, what is that? No? No, no, I mean I you're thinking of something. What is the thing I always.
I always joke with my friends and I would love to just you know, my retirement plan on basically after all of this is to go be like, I don't know, an assistant to someone like Wes Anderson who makes these incredible films that you know, I adore and I feel, you know, and and really just create these very interesting worlds, and I feel like I just would want to, you know, maybe get his coffee or something.
Do you think of going into the movies when you were whatever in college or something?
I mean in high school, I actually spent all my time in drama, right, basically you know, doing school plays, doing musicals, I mean, all that stuff. So and I really thought up until the point of I was making decisions to apply to college, you know, I thought that I would go into basically theater and you know, do theater, do movies, whatever. And then I just, you know, as I was actually applying, kind of had a revelation of do I really want to do that, you know, for
the rest of my life? It actually seemed difficult. Not that what we're doing now isn't difficult, but it seemed difficult in a way that maybe was difficult. You know, even as much work as I could put in, right, it's it's not necessarily you can't necessarily project the outcome, and even at that time, you know, it was sort of taking a step back and saying, you know, what
can I do? What do I want to do? Which allows me to sort of build create, you know, and make things and produce things, but something that could really have a meaningful impact right on the world. And so that kind of that then led me to engineering, you know, engineering with biology and and and really that sort of started that route as I went into college.
I've taken up enough of your time. Is there anything else you want to say?
No, I think you've done a great job of directing the conversation. So hopefully it's you know, then at a good level for the Are.
They not at all worried? Sometimes at the end of inner, I'm like, how am I going to make this work? Guy? This is gonna be an easy one. This is great.
Thank you, absolutely, thank you.
Christina Smolke is the co founder and CEO of Anthea. Today's show was edited by Karen Chakerjee, produced by Edith Russolo, and engineered by Amanda K.
Wall.
You can email us at problem at pushkin dot fm. We are always, always, always trying to find interesting new guests for the show, So if there's somebody who think we should book, please let us know. I'm Jacob Goldstein and we'll be back next week with another episode of What's Your Problem.