The printing press for biological data (Sterling Hooten)

Introduction TimestampsTranscript Watch on Youtube, Apple Podcasts, or Spotify.After having written long-form essays over a weirdly diverse number of areas of the life-sciences, I am increasingly confident in my status as someone who knows a little about a lot of things. But every now and then, you meet someone who casually reveals to you an entire subfield who, up until your conversation with them, you’d never even thought of before. This happened to me when I met Sterling a few months back. We met in the elevator as we were both leaving an event, and by the time we’d reached the bottom floor, the conversation had become so interesting that we stood in the lobby for an hour as I pestered him with more and more questions. Sterling runs a company called Iku Bio. Iku ostensibly does something quite simple: it helps biologics manufacturers figure out what to feed their cells. This is called media optimization, and it is done in an astonishingly old-fashioned way. An engineer runs a handful of experiments in a benchtop bioreactor the size of a Fiji water bottle, waits days for analytical results, and repeats, maybe three or four times before timelines force them to stop searching.Sterling’s solution was to use printed circuit boards (PCBs)—the same green wafers inside your phone and your microwave—as the substrate for microfluidic bioreactors. Because PCBs are made via lithography, you get complexity for free. Because they’re already mass-manufactured at planetary scale, you inherit sixty years of cost optimization. And because they’re literally designed to carry electrical signals, you can embed sensors directly into the thing rather than cramming them in after the fact. The result is a device that costs $8 per experimental lane versus $20,000 for the nearest comparable microfluidic system. And there are many, many ways for to improve from here on out. This conversation covers the full stack: what cell culture media actually is and why it’s so much more than sugar water, why biologics manufacturing has more in common with semiconductor fabs than chemistry labs, how Sterling arrived at PCBs, and at the end of the talk, why he thinks a fair bit of lab automation is “philosophically a crime.” [

00:00:48] Introduction[00:01:26] What is Iku Bio?[00:05:00] Media optimization as the biggest lever[00:06:23] What actually is media?[00:13:07] Fetal bovine serum and the move to synthetic media[00:15:10] Walk me through a media optimization workflow[00:18:49] Why biologics manufacturing is closer to semiconductors than chemistry[00:21:50] Matching the phase three batch and generics[00:24:12] The 200-dimensional search space[00:37:02] Printed circuit boards as a medium for microfluidics, and the utility of lithography[00:40:48] Anatomy of the Iku device[00:57:09] What sensors are on the device today?[01:01:36] How do you use the Iku device to perform media optimization?[01:14:44] Does media optimization survive scale-up?[01:24:32] $8/lane vs. $20,000/lane: the economic utility of Iku’s device[01:32:05] Why PCB microfluidics didn’t exist 10 years ago[01:39:24] Who is the customer?[01:43:14] What is the ultimate goal of Iku?[01:49:07] What does the validation evidence need to look like?[01:52:14] What would you do with $100M equity-free?[01:57:31] Lab automation is in a strange place right nowAbhi: Today my guest is Sterling Hooten. Sterling is the founder of Iku Bio, where he is building a microfluidic bioreactor built on a printed circuit board that cultures, senses, and streams biological data in real time, claiming 10,000x higher experimental throughput at a 100x lower cost.

It is one of the most niche areas of wet lab automation that I think I’ve ever discussed on this podcast, and I don’t think I would’ve ever learned about it had I not stumbled across Sterling at an event a few months back where we had a conversation that was so fascinating that I immediately wished we had filmed it. Sterling, welcome to the podcast.Sterling: Thank you for having me. Very big fan. Really enjoy your articles.Abhi: Thank you. So I’ve given a brief introduction of what you’re working on at Iku, but I’m sure I oversimplified some things. I’d like to hear your own pitch for what you’re doing there and why is it so valuable.Sterling: So the largest problems of the 21st century — things in medicine, for climate, for material optimization — all of these are predicated on our ability to manipulate and control living matter. So advancing our understanding of biology is just so fundamental to these problems in the future, and yet the tools that we use right now to interact with biology are primitive. They’re primitive in an absolute sense, and they’re primitive in a relative sense to what we could be doing. At its core, biology is time varying, it’s parallel, and it’s sensitive. And yet the tools that we use right now — that interface destroys at least one of those properties. And in principle, advances in AI also would be an excellent connection with biology. But that interface is fundamentally broken. So lab automation right now is stuck at the Petri dish and the microtiter plate level. It’s equivalent to handwriting manuscripts in the 15th century, sometimes. And so what we’re building is a printing press for biological data. And the way that we’re doing that is we’re rethinking that interface between compute and biology, and we’re replacing traditional microfluidics with a printed circuit board that allows you to embed the fluidics — cells can live inside of it. And that allows you to communicate and control cells in a way that has not been possible before at high throughput. And the largest application that we see for that is in biologics manufacturing. Right now, biologics — it’s a half a trillion dollar industry and it’s supply limited. So every year, Samsung Biologics has to build a new $400 million facility. The reason they’re doing that is because you can only get so much out of a traditional fab plant.

They’re closer to silicon fabs actually. And the largest lever that they have is in yield — so how much can you get out of these things, are they producing, and also what are the costs. The core of that comes down to literally how many of these dynamic cell culture experiments can you run. And that’s a process called media optimization. And it ends up that that one problem ends up being connected to this half a trillion dollar industry.Abhi: So to paraphrase, if I wanted to increase biologics manufacturing by an order of magnitude — at least my capacity to produce like antibodies and the like — the lever that is most easily pushed on and most likely to give you the most bang for your buck is media optimization.Sterling: It is the most bang for your buck. You are unlikely to get 10x on that. What you’re looking at is how much can I produce per unit time, and then how consistent is that. And if you can produce more per unit time, you get higher throughput for the entire facility. And then if you have more stability in the product — for biologics and for things that go in our bodies — that’s a desirable outcome.Abhi: And so my conception of these bioreactors that are producing antibodies is you have a bunch of CHO cells maybe sitting in a very large tank. They’re sitting in a fluid of media and they’re constantly just excreting out these antibodies that are later purified. Iku comes in at the step of deciding what media to actually put into this tank. Is that fair to say?Sterling: Correct. Yeah.Abhi: What is — well, like I’ve never worked in a wet lab before.Abhi: My conception of media is that it is sugar water that cells are generally fine with drinking up. I’ve learned that this is incorrect and I’d like to hear your take for what actually is media.Sterling: I would say that that is a very limited view of what media is — not incorrect in that, if we were talking about media for growing yeast, sugar in water is pretty close to sufficient. But the more powerful way of thinking about media is that it is a very high dimensional control surface for what you can get cells to do, right? Cellular communication comes through things in the media, right? The media actually is the communication channel in a sense between cells. It’s also what carries nutrients into the cells.

In mammalian cell culture, it’s closer to serum in blood. So it has either many different types of proteins in it. It’ll have different metabolites. It’ll have salts. In defined media it’ll have buffers to keep the pH. It basically has a lot of components — and there are hundreds of them really, down to things like magnesium. And each of these are really communicating and interacting with the cells. And they also work across different time periods. So you’ll have growth media, which is when you’re building up the cells, and then there’s media when you really just want them producing these particular things. And right now, if you buy or produce media internally, it tends to be connected to a particular clone or particular cell line. And so you will optimize the media for that particular cell line, or you’ll optimize media for — if you’re growing neurons. And so every — it’s complicated enough and important enough to the results that you get that exploring it is very valuable.Abhi: Like I know that there are a few companies that have popped up claiming to technically redesign cell lines to make them better at biologics manufacturing. Does that also demand a change in media?Sterling: It can demand — the key thing is that the biologics that we are producing now are becoming more complicated, and that is making media optimization more difficult. So you do tend to pair the cell line with a media line, both for repeatability and ease of use, also just for commercial reasons — that’s a better business. But you can — what really happens is you tend to take a standard growth media or something off the shelf, and then you will customize it for this particular thing that you’re trying to make. Because ultimately, productivity is really the interaction of these three or four things: it’s the cell line, it’s the media, it’s the process conditions or the tank that you put it in, and then the actual compound of interest and things that you’re trying to do.Abhi: You mentioned earlier about like media is both a way — like nutrients for the cell — but is also the substrate upon which they actually communicate with each other. That second part was surprising to me. I did not naturally conceptualize cells in a tank actually talking to each other while they’re churning out antibodies.