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Translating exciting discoveries into next-generation technologies fuels the mission of the Center for Synthetic Biology (CSB) at Northwestern. Since its inception in 2016, the CSB has produced several start-up companies that have contributed to the University’s entrepreneurial ecosystem. One example is Opera Bioscience, a promising new startup cofounded by Danielle Tullman-Ercek, Professor of Chemical and Biological Engineering. Last year, Opera Bioscience joined Northwestern’s multimillion-dollar technology accelerator Querrey InQbation Lab to hasten the commercialization of its proprietary technology.

CSB caught up with Tullman-Ercek, Co-Director of CSB, recently to learn more about the science behind the startup and her journey to becoming a first-time entrepreneur.

What is the (idea) or science behind Opera Bioscience? What problem does it solve?

For a long time, my lab was studying the process of protein secretion, which is how bacteria move proteins out of the cells. We found an incredible system in Salmonella that could secrete very specific proteins without secreting anything else that we don’t want. As we were figuring out how to use secretion, we also learned more about the “state of the art” in industry for making protein. Most companies that made protein in bacteria were using a process that still required breaking open the cellular factory after filling it to the brim with product. That damages the product, and making it functional again was possible but very difficult, much like unboiling a hard-boiled egg. In contrast, our secretion process is like adding a loading dock to a factory in which only the finished products are sent out onto the truck.

We then found that if we add a tag to the protein we want to make (much like adding a zip code to an address), the Salmonella cell’s ancient machinery will send it out of the cell. Once it does so, it’s still soluble and functional. All we have to do is settle out the cells and collect all our protein product. The seed for Opera Bioscience was when we realized just how important the secretion capability could be to industrial production – how much faster and cheaper the production process could be if our secretion system were used instead the traditional process.

How is the technology useful? 

Proteins are used everywhere in society, and not just in our food. Every day, people are using proteins, whether or not they know it, in their consumer goods. For example, detergents that get rid of grass or oil stains use specific enzymes engineered to work at washing temperatures so that they can still break down the stain. Clothing fabrics like silk are made of proteins. We put protein such as elastin, collagen, and keratin on our skin and hair. And that is not to mention how much we use in medical applications such as insulin for diabetes or cancer-targeting therapies! All of those proteins have to be made. This is not something you can make synthetically very easily or cheaply, if at all. Instead, protein is made by living cells such as bacteria. The only trouble is that cells make lots of proteins to run all the cellular life processes. So, you have to separate the protein that you care about from all the other proteins. That’s like picking out the Lego block you need next to build your project from a box full of different Legos. . There’s a sorting process that has to happen and that takes time and money.

How do you scale up the technology?

We had this system that we knew could do this job, but it only makes a very small fraction of the amount needed.   When we started working on it, it was making around 10 to 100 micrograms of material per liter. We need at least a gram per liter in order for it to be commercially viable —that is thousands of times more than what we were getting in our best-case scenario!

To make that jump, my lab first tried to understand how the system worked natively. Part of that was figuring out how it turns the secretion system on and off. This is important because if you have your cells in a flask or in a reactor to make the protein, that’s not its native environment and the secretion system is on standby. Thus, we first figured out how to turn on the system, which gave us a hundredfold increase in how much protein we produced. Then we figured out other things it liked in its environment like phosphate and sugar.  We also made mutations to make it more efficient. We now are at about half a gram per liter. We came a long way—we now make 1,000 times more than we did to start. As we were thinking about launching Opera, we knew we just needed to double the amount to really be commercially useful.

Through our interviews with industry workers who make protein, one of the things that we learned is that the amount of bacteria that we grow in one liter in a lab in academia is not the amount that industry is growing in one liter in their special large-scale reactors called fermenters (the same kind of tanks used to make beer). In fact, they usually have about a hundred times more cells when they grow in fermenters, so it turns out that we probably surpassed our goal a while ago if we had put our system in the same kind of conditions that industry uses.

That was the tipping point. We asked, ‘Why aren’t people already using this?’ Our industry connections answered that they weren’t using it because it was a new technology and there is a lot of risk when trying a new technology. Our path was clear. We worked with INVO to patent it and start demonstrating how to use it ourselves.

When did you begin the startup process?

I started working with INVO (Northwestern’s Innovation and New Ventures Office) around 2018. Lisa Dhar (INVO’s Associate Vice President for Innovation) was teaching a class at Kellogg and needed case studies for technologies that were still in the labs at Northwestern. She came to me and asked if I’d be willing to put together some slides and pitch them to her class to see if anyone wanted to work on my particular idea and I jumped at the chance.

When I did that, one of the students in that class, Gerry Sapienza, who’s now our CEO, was super excited and recruited a whole group of people who helped develop some of the early business models and did a lot of the early interviews to figure out how this could be used and what we would need to do in order to be successful. He started coming by the lab just to better understand the science and technology. When he graduated, he said, ‘I would love to help you.’ That coincided with when my PhD student on the project, Julie Ming Liang, was preparing to graduate and she also was really interested in founding the company. When she graduated, we moved Opera into the InQbation Lab and she became Chief Scientific Officer.

What stage is the company currently in?

Opera is still negotiating the license for the technology from Northwestern. When that goes through, they will have it to then sell product directly or sublicense the system to companies to use themselves. We have done close to a thousand interviews with different industries [for example, cosmetics, paper, detergents, and animal-free meat] because this is a platform that could be used for almost any consumer product. We have this method for making whatever protein you want us to make faster and cheaper.  We’ve been discussing the platform with pretty much every company you can imagine and we’re still in very serious talks with several of them.

We were able to obtain pitch competition money and funding from the NSF SBIR program to help demonstrate our technology works for proteins that consumers need, and using processes that are industry standards. In addition, Dr. Julie Liang, Opera’s CSO, was awarded an NSF Activate Fellowship which is for new scientists who are entrepreneurs and starting a company.  It embeds them in a program to help introduce them to all the other aspects that they’ll need to learn, besides science, in order to be successful in building a company.

Between all of those things, we had enough funds to hire our first non-founder employee, who’s doing a lot of experiments at the bench. We have plans to hire another person very soon.

Did you always set out to be an entrepreneur?

No.  It became this way mostly because I thought, ‘Why did I work on understanding how this system works for 10 years if it’s not really going to be used?’ It was really sad to know that it was unlikely to be picked up by someone unless we put it out there ourselves because companies can be so risk-averse. I wanted this really interesting science to actually make an impact. It won’t unless scientists start doing some of that translation and working with the people in business to do it. And that’s something that Northwestern does really well— connecting the scientists with those who have the expertise to help us make sure it can go out into the world.

by Lisa La Vallee

Photo by Zachary Ochinko