Hard Biology: Viscosity
There's a million reasons why biology is hard tech. Today we're talking about one of them: viscosity.
Transcript
The foundry at Ginkgo Bioworks is an incredible platform for engineering biology. It's full of sophisticated tools for reading and writing DNA. It's equipped to solve the hardest problems in biotech. But if you wanted to think about it as a place that is just really good at moving around water, you wouldn't be far off.
Because it turns out that many of the operations required to engineer biology are about moving water accurately and efficiently. And when you add biology to water, things get complex pretty quick. Viscosity is one measure of this complexity. It describes the thickness of a liquid, like a syrup or a motor oil. More generally, biological substances have all kinds of strange physical properties that make them hard to handle.
Biology is sticky. It's slimy. You might think that should be obvious to anyone who has a human body. I mean, have you seen what comes out of this thing? It's disgusting. But somehow the physical reality of dealing with biological goop is something that catches people by surprise. I don't know if it's the hardest challenge to engineering biology, but it might be the most underestimated.
People don't respect viscosity as an engineering problem. I think it's partially because of the way biology often gets promoted as a technology. Look at the popular images: Clean laboratories. Shiny metal bioreactors. Fancy instruments with buttons and lights. Somewhere back in history, somebody decided that if you want to look high tech, you have to hide the slime. But people who are new to biology quickly learn that, more often, the slime is on the cutting edge. You need to win at slime.
It isn't just an issue for beginners. You've probably heard about what they call the replication crisis in biotech R&D1. Many published results from academic labs, including top labs with great reputations, aren't reproducible in other labs. It's a complex problem with many causes, but in my opinion, the complexity of liquid handling is a big contributing factor. A lot of work in biology is still done using manual pipettes. Moving viscous liquids by hand uses a certain finesse that just doesn't replicate in different hands.
Think about a relatively simple piece of biological liquid handling: making an omelet. You crack two eggs. Add a teaspoon of diced herbs and a pinch of salt. Give it a whisk. Cook it up. Flip it over. When the pro chefs on my TikTok feed do it, it comes out fluffy and perfect. When I do it, it's lumpy and burned.
Why is omelet biotech not reproducible? Because the written recipe for an omelet doesn't transfer the subtle manual techniques that a chef learns from personal experience. Luckily, we don't need omelets to be exactly the same every time. But for biotech that is what we want.
Obviously, automation has to be part of the answer here. Modern liquid handling robots are not quite as agile as a human hand, but they're pretty good. You can pipette fast for thinner liquids or you can pipette slowly when liquids are more viscous. You can pipette from the top of the liquid level in a well or from the bottom. You can mix the liquid up and down several times in case it has particles that can settle.
You can touch the tip on the sides of the well to shake off excess drops. There's lots of parameters to adjust. And the pipetting robots are just one of many instruments we use that move water.
With every new workflow, it takes time to get the settings just right. But once they're locked in, you can reproduce them exactly for as many operations as you need. That's a big advantage of Ginkgo's foundry model. A lot of our operations are repeatable. All that work you would have to do to program a particular automated process, if you work with us it's probably already good to go.
Another way we handle the challenge of viscosity is by engineering the biology itself, for example with our low-viscosity strain of Aspergillus. Aspergillus is a type of fungi that's good for making proteins or enzymes. We like it for food ingredients or for other applications where you want to make a lot of protein at a low cost.
We've seen this thing reach very high production titers - even beating out strains of yeast like Pichia that are also good at this. And aspergillus can secrete proteins directly into the media, which means you don't have to break open the cells to purify them. It's not crazy to get 1 gram per liter per hour levels of production, depending on the protein.
So aspergillus has always been an attractive organism for manufacturing proteins at scale. Except for the viscosity. Like a lot of fungi, it grows in these long stringy structures called hyphae. Like a lot of microbes, it has a tendency to secrete polysaccharides and other sticky molecules to form protective biofilms. As a result, it is really hard to mix. You can't get enough oxygen into the fermenter tanks because the damn things get too viscous to stir.
So at Ginkgo, we've developed a low-viscosity aspergillus that's a lot easier to handle. If a typical aspergillus strain gets thick like toothpaste, our strain is more like apple sauce. It's not thin, but it flows. That means more consistent fermentation, better oxygen transfer, and better scale-up for commercial bioproduction.
These properties also make it easier for us to do the strain engineering. Wild-type aspergillus at high density barely even counts as a liquid. But the low-viscosity strain handles more like a conventional laboratory yeast. As we've brought this thing on board, we developed all the genetic tools we need to work with it effectively. We've got an off-the-shelf library of genetic parts, strong promoters for making proteins, we can do gene editing, the full stack.
Viscosity is a very biotech kind of problem. Every biological substance is a little bit different. The only way to handle it is to build and optimize a real physical workflow. At the Ginkgo foundry, we've set up a lot of these workflows and we're good at it. We measure, mix, transfer and transform all kinds of watery cell juice. We do it, so you don't have to.
https://en.wikipedia.org/wiki/Replication_crisis