Category: Services

Ginkgo Bioworks’ cell engineering platform lowers the bar for entry into developing products through metabolic engineering.

High-throughput strain design and testing on industry-leading chassis strains, paired with AI-enhanced enzyme engineering tools provides Ginkgo’s partners rapid prototyping and development. Nádia Parachin, Senior Director of Business Development at Ginkgo discusses how this streamlined process enables quicker market entry, fostering a lower barrier to bringing new products to market.

Humans of Ginkgo Bioworks is an interview series featuring Sudeep Agarwala interviewing some of the brilliant folks at Ginkgo to learn more about the technology that makes our work possible.

Sudeep Agarwala: You’ve run projects for quite some time at Ginkgo, but before that, were spanning both academia and industry, correct?

Nádia Parachin: Well I’ve been at Ginkgo for almost four years now, but you’re right–I came to Ginkgo from Brazil. In Brazil, I was a professor at Universidade de Brasilia and at the same time, I was the Co-Founder and CEO of Integra Bioprocessors. Integra used metabolic engineering to convert agro-residues (glycerol, for example) into high-value chemicals. And in fact, two of the technologies that we co-developed at Integra and UnB was a microbial strain producing PLA from glycerol and another strain producing Hyaluronic acid from sugar.

But that also naturally led to this position at Ginkgo. Since 2020, I have run quite a few projects at Ginkgo through the Foundry in yeast–Saccharomyces cerevisiae. What can I say? It’s my favorite yeast.

SA: Recently you’ve made an interesting shift–you’ve moved over to the commercial side, thinking about how Ginkgo’s platform can be applied widely to different companies?

NP: What is most impressive to see at Ginkgo during these years is not only once but–to my knowledge–at least a few times, the production of molecules that have never been made in a microbial host before. I’ve seen the same for enzymatic reactions. At Ginkgo, we demonstrated reactions not found in nature, truly contributing to the company’s mission of making biology easier to engineer. 

The reason for these success stories is the combination of our physical platform–automated, high-throughput strain design, construction, and testing– paired with our digital assets– incredible database of enzyme engineering experimental results and now AI-enabled engineering tools.  An equal player in this is the expertise of the people who run these workflows and design the experiments at Ginkgo. We have a collection of people who have deep knowledge of the different microbial hosts and have been working for years on critical pathways and developing tools to make this engineering possible.

What I find exciting about being on the commercial team is that my team’s technical expertise can be teamed up with people who have a real understanding of the market, resulting in tailor-made offers for what the market demands. It has been a fun journey, and I’m thrilled to be part of this team.

SA: Maybe to go into more detail here, what exactly does Ginkgo provide to its partners?

NP: Ginkgo provides our partners with a head start–partially because of the platform and our knowledge-base–technical assets we’ve collected over the years. So if a partner comes to us and wants to make an innovation in their field, they don’t have to invest in their own lab space, expensive specialized equipment, etc. They can get started very quickly by leveraging Ginkgo’s R&D capabilities and running experiments for a fraction of the cost of building a lab from scratch. This means they have a lower barrier to explore which  product has the potential to make a real difference in the market. 

We’re also providing value to the companies already in the field, who are already doing synthetic biology and fermentation. These companies know what they are doing in terms of their technology, their market. They have a good understanding of their processes for commercialization. But with our expertise, we can take on newer, earlier-stage projects instead of these companies having to rearrange their internal R&D: let us do your innovation, and when the technology is mature, you can incorporate it into your pipeline–you do the manufacturing and the commercialization.

SA: I’m curious about the difference between Ginkgo and CROs. When does it make sense to come to Ginkgo vs. say, going to a CRO?

NP: We see this question come up all the time. The most important difference is that besides our platform and a proprietary database, Ginkgo has developed and owns what we call “chassis” strains: microbial hosts that have been modified for increasing flux throughout key metabolic pathways.

Take the shikimate pathway, for example. This pathway can produce multiple molecules, ranging from building blocks for polymer production to flavors, fragrances, and nutraceuticals.

When you go to a CRO to engineer a product off the shikimate pathway, you have to start from scratch to develop dedicated enzymes for your target’s pathway. In parallel, you also have to develop a strain that will have a high flux through the shikimate pathway to get your product to your target titers.

But when you’re working with Ginkgo, our starting point is lightyears ahead. We’ve already developed the base assets, our ‘chassis’ strains that have flux through the shikimate pathway at very high levels. So now we dedicate our work to the specific part of our customer’s pathway that converts this flux into their target molecule. And because it’s only this part, we can deliver both prototyping and strain development faster than any other CRO. 

I’m talking about the shikimate pathway here, but it also applies towards fatty acid metabolism, terpenes, any range of pathways that you’re engineering off of. You’re not starting from scratch–you have the starting strain, the platform, the enzyme engineering capabilities, and that gives you a head start towards commercialization. 

SA: So this is a compelling reason for leveraging Ginkgo’s platform, but I’m curious what happens if too many people start to do that. Like you’ve acknowledged, there’s a big market in metabolic engineering for small molecules. How does Ginkgo think about protecting information between different companies who are coming to Ginkgo?

NP: This has come up a few times as a major concern from people who are talking to us. We’ve had partners who have said “Look, I know you guys have a project with my competition. Can you guarantee that there’s not going to be any sharing of my information?”

And one of my arguments for the companies in industrial biology has been that we aren’t just doing small molecules: we have pharmaceutical companies on the platform–that’s the standard that we’re working with to ensure that there’s no sharing of information between different projects for different companies. We have that capability and we take it very seriously. We’ve developed systems internally that flag information so that it cannot be shared and that data that results from one customer’s project cannot be shared.

The entire point is that Ginkgo prepared itself over the years to be positioned at the cutting-edge of synthetic biology technology, and we’re working towards utilizing the platform to enable the sustainable production of biomolecules applied to several industrial sectors. It’s not just about engineering strains, it’s also about creating a bioeconomy and seeing it thrive. And we’ve made it possible so people can develop their strains and bring their products to market with confidence that they’ll be competitive.

Nádia Skorupa Parachin, Ph.D., is Senior Director of business Development at Ginkgo Bioworks, leading the Industrial Biotechnology sales team for the production of small molecules. Nádia brings over 15 years of experience in synthetic biology, metabolic engineering, and project management. She has previously served on the technical team at Ginkgo as a Senior Program Lead, engineering and delivering custom strains for Ginkgo’s partners. Before joining Ginkgo Bioworks, she was CEO of Integra Bioprocessors and a professor of biotechnology at Universidade de Brasilia (UnB).

Yarrowia lipolytica has become a workhorse for metabolic engineering of molecules derived from fatty acids.

In cars, a chassis is a base frame to house the engine and working parts. Program Director Christian Lorenz discusses how Ginkgo developed standardized strains, workflows and DNA parts for the yeast Yarrowia lipolytica to help launch innovative biological engineering campaigns.

Humans of Ginkgo Bioworks is an interview series featuring Sudeep Agarwala interviewing some of the brilliant folks at Ginkgo to learn more about the technology that makes our work possible.

Sudeep Agarwala: I’m speaking from my personal bias, but when I think of yeast I usually think of Saccharomyces cerevisiae. Why is Yarrowia lipolytica such a powerful tool?

Christian Lorenz: Sure–I think there’s a good reason you don’t think of Yarrowia when someone mentions yeast. Most people would probably agree that Yarrowia is still a non-traditional yeast, but given how important it is in industrial biotech, there’s a lot more interest in the yeast for academic circles.

Basically, as the name suggests, Yarrowia lipolytica has been of interest because of its ability to accumulate lipids, or fat. We’ve seen natural strains accumulate 20 percent or more dry cell weight in lipids–I believe there are some reports of 40%, even. Some engineered strains can even have a higher content of fats.  So Yarrowia is an expert in making fat and has a high flux through the fatty acid biosynthesis pathway.

This pathway is upregulated when the cells experience nitrogen limitation–there’s a starvation response that triggers lipid production. They utilize the carbon in the media, usually in the form of glucose, but in the industrial setting it can be something cheaper like ethanol, glycerol, acetate, or even different types of oil, and start accumulating fat, which are stored in lipid bodies in the cell.

SA: But there are a lot of yeasts that produce fatty acids–what’s so special about Yarrowia that it’s able to do it at such high levels?

CL: This is something that’s in common with an entire family of oleaginous yeasts, they’re called. In these yeasts, the precursors for the fatty acid synthesis pathway–acetyl CoA, which converts to malonyl CoA. In oleaginous yeasts, citrate is produced in the mitochondria; it is shuttled into the cytosol, where an enzyme, ATP citrate lyase, converts it into acetyl CoA, which leads to fatty acid biosynthesis. The flux through this pathway is much higher in these yeasts.

SA: This lifecycle seems pretty great for metabolic engineering — I know Yarrowia’s a workhorse for metabolic engineering off the fatty acid production. And in protein production, it’s great for lipase production.

CL: Lipases, and a lot of other hydrolytic enzymes too. But there’s an interesting use in small molecule production as well: because of the metabolism, Yarrowia is a good acid producer and that usually means that it can tolerate low pH in fermentation. That’s important because for some yeasts, they die at low pH. So when you engineer these yeasts for some small molecules that drop the pH, you have to add a lot of base to your fermentation. That’s not the case for Yarrowia, which we’ve seen do well as low as pH 3, even.

SA: That’s the good — I want to talk about the ugly, though. Yarrowia is known as a dimorphic yeast, meaning it has ovoid cells, but can also form these filaments that can cause real issues when it comes to fermentation. How do you deal with that?

CL: This is a really good point. First of all, we have a collection of more than 30 different naturally-occurring strains of Yarrowia at Ginkgo that we’re allowed to engineer with. Each of these strains are Yarrowia lipolytica, but they differ a lot in how they behave in how we engineer them, and how they behave in different fermentation processes. So for any particular engineering project, we have a wide choice of strains that we can test to see which ones will behave the best in our process.

SA: I feel like we’ve buried the lede — Ginkgo has more than 30 different wild Yarrowia strains?

CL: Sorry — yes. More than thirty, and we’ve gotten them being very careful about restrictions on freedom to operate and IP restrictions. And we’ve done a lot of work characterizing them: there’s the obvious questions about how they behave on solid medium on a petri dish vs how they grow in a liquid medium. But we’ve tested them further: how much flux do they have through the fatty acid biosynthesis pathway? In different fermentation conditions how tolerant are they to different process conditions? how well do they tolerate different pH? etc. We’ve gained quite a bit of information for them, so we can make intelligent decisions about how we deploy them in different engineering projects.

SA: What does it take to be able to genetically engineer more than 30 different Yarrowia strains?

CL: Well, we think about strain engineering in a Design-Build-Test-Learn cycle.

In terms of Design, we have standardized DNA tools that we know will work in most, if not all, of these strains. That is, we have standard promoters, terminators, drug selections on these engineering tools. And they’re targeted to parts of the genome that we know are easy to target.

That leads to Build, where we’ve developed methods of culturing and effectively introducing this DNA into these strains pretty effectively–transforming a wide range of these hosts in high-throughput is a pretty standard operation at Ginkgo.

For Test, like I mentioned before, we have a good understanding of how these strains behave in a wide variety of conditions–liquid media, solid media, and fermentation vessels. We know how to cultivate these strains in high-throughput so we can measure how much product–small molecule, protein, etc.–they’re producing.

SA: I hope you don’t mind the direct question, but at Ginkgo we refer to “chassis strains” when we’re developing an engineering plan. What exactly is the Yarrowia chassis at Ginkgo?

CL: I think we’ve done a good job summarizing that here, actually. A chassis is a frame or a housing for a piece of technology. Part of our engineering efforts at Ginkgo have been to make that framework in Yarrowia: we have strains, genetic tools for targeting and expressing DNA, protocols for building libraries of yeast strains in high-throughput, and protocols for testing these different strains in high-throughput. There will be some edge cases, always, but with these basic elements form a very powerful framework for biological engineering.

So when a new project comes in, we don’t have to think about developing things from scratch or bringing in new yeasts and spend a lot of time testing them or developing processes for them. Instead, we have our engineering chassis: we’ve built the engineering infrastructure for Yarrowia so that our customers can bring exciting products to the market fast.

Christian Lorenz came to Ginkgo Bioworks after completing his PhD work on bacterial protein secretion systems with Ulla Bonas at Martin-Luther-Universität Halle-Wittenberg, and post-doctoral work on Pseudomonas aeruginosa in the lab of Stephen Lory at Harvard Medical School in Boston. At Ginkgo, he is an organism engineer specializing in metabolic engineering for small molecule production in bacteria and yeast systems.

Ginkgo’s Protein Services leverage a diverse technological platform to provide support our partners’ R&D.

Sneha Srikrishnan, Senior Director of Business Development at Ginkgo, discusses how Ginkgo’s business model customizes partnerships to align with the developmental stage of partners’ products, offering tailored R&D services from strain engineering to fermentation optimization. 

Humans of Ginkgo Bioworks is an interview series featuring Sudeep Agarwala interviewing some of the brilliant folks at Ginkgo to learn more about the technology that makes our work possible.

Sudeep Agarwala: Sneha, you’ve been at Ginkgo more than seven years and have done everything from strain development workflows in the foundry all the way to talking to customers about how Ginkgo approaches protein expression issues. 

Sneha Srikrishnan: Well actually, I’ve been thinking about protein production for my entire professional career–I researched this as a graduate student and postdoc and you’re right–when I first came to Ginkgo, I was working on developing a lot of the early workflows in the foundry for engineering different types of yeast. It’s been incredibly gratifying seeing those workflows grow into what Ginkgo’s offering now and it’s also why I’m so eager to talk about Ginkgo’s place in protein production in my current role in business development at Ginkgo.

SA: I know you’ve talked here about how Ginkgo works with partners in the protein space. I’d like to get a sense of how the partnering work–an earlier-stage product may have a very different scope of work associated with it than a more mature product that is already out on the market. So how does a company’s stage in R&D play a role in how we partner with them?

SS: We’ve thought about how to work with a wide range of partners in the protein space and the different stages of products that they’re working on. You’re right that early-stage products may require more extensive R&D in terms of strain engineering or other aspects of product development. Add to this, many early-stage products, either at start-ups or at larger, more established companies, may not have a lot of cash to outsource R&D–either because people are working on these early-stage products as a preliminary proof-of-concept to see if it has legs or because people are still working on funding for their company.

Late stage products can have a different scope associated with them. And by this, I mean, projects that are already on the market, so maybe there’s less strain development and more emphasis on fermentation optimization, processing, with less of an emphasis on strain engineering.

In my previous conversation, I’ve talked about how Ginkgo’s Protein Services’ Offerings are aimed to help projects at a wide variety of stages. But there’s another important point to discuss here in terms of how we try to maintain flexibility in our business model with these service offerings, and structure it so that we are tying our success to the success of our partner.

In general, we divide the cost of a project into two buckets. There’s an R&D fee, which we don’t generate margin from. The second bucket is downstream value–and this is where we tie our success to the success of our partners.

Realizing downstream value can be in the form of royalties on sales, a flat percentage of revenues, lump-sum payments on commercial milestones, or any combination of these. Or, for whatever reason, if it doesn’t make sense to have this payment tied to sales, we’ve been able to find ways to solve these situations as well–single payments, or a single payment broken up into different chunks; we try to be flexible on how this downstream value is realized and we try to work with our partners on how this can work.

What I’m trying to emphasize here, though, is that Ginkgo wants our partners to be successful, and that we’re willing to work with our partners to index on that success.

SA: I think maybe you’ve answered this question indirectly, but I want to make sure: when does it make sense to come work with Ginkgo versus, say, a CRO?

SS: I like this question because I get it in different ways from many potential partners. I think of it like this: companies can go to CROs with a very defined service that they are looking for–in many instances, this is the kind of work that companies have the capability but not the bandwidth to do or can’t justify the expense to do in-house for a project that might be in its very early stages. 

Ginkgo’s cell engineering platform is different. The goal of developing this platform is to bring a wide range of technologies to bear on a single project; and in some cases we’ve combined part of the platform into our Service Offerings, which makes sure that we’re providing state-of-the art technology on our partners’ R&D.

SA: And, I suppose, there’s an effect of streamlining the work through Ginkgo in these Service Offerings, versus having to coordinate with a lot of different CROs or academic groups.

SS: Exactly–there are efficiencies when you’re bringing a product to market with Ginkgo, and this is what makes it a great place for companies interested in end-to-end research and development. In progressing your project from early stages–discovery or early strain development–all the way to fermentation optimization and scale-up, there’s an efficient knowledge-transfer that comes between the different teams working on your strain that can really shave a lot of time off your commercialization process. Imagine if instead you have to tech transfer from and to a different CRO every time you needed to move to the next stage of your project.

And there’s one other point that I think is worth mentioning here–that efficiency brings with it flexibility. Let’s say for example you’re developing a strain using rational engineering methods and are hitting a wall with reaching the target titers. Ginkgo can quickly move to unbiased engineering methods without having to identify a partner who can do this work.  We know how to do this quickly because they are already part of our broad platform: the teams for rational engineering and unbiased engineering collaborate to provide new direction to the project (sometimes they’re even the same people). And this is how we can quickly shift gears to this new direction in the project.

We think about this efficiency in our platform in terms of “more shots on goal” at making a project successful. I think this is something to really emphasize: you can potentially mitigate a lot of technical risk by working with Ginkgo. Having many workstreams easily accessible in one place allows you to try different things quickly as you move forward to commercialization. And at a place like Ginkgo, we’re there to support the development that needs to happen so you can focus on the product-facing work needed to commercialize your protein.

Sneha Srikrishnan is Senior Director, Business Development at Ginkgo Bioworks, leading Protein sales & Product management. She previously served on the technical team of Ginkgo as a Sr. Director of platform technology for enzymes and protein production. Prior to Ginkgo, Sneha worked at Gevo, Inc. as a scientist developing yeasts for commercial production of isobutanol. She has over a decade of industrial experience in successfully delivering synthetic biology-based solutions within the nutrition & wellness space, in sustainable fuels, waste valorization and environmental remediation, and holds patents in these areas. Sneha graduated with a Bachelors in Chemical Engineering from the Indian Institute of Technology, Bombay and earned her Ph.D. in Chemical and Biochemical engineering from the University of California, Irvine. Sneha is passionate about food security and circularity.