Photo by David Clode on Unsplash
It’s no secret that biology is unpredictable, random and sometimes messy. This is precisely what gives living organisms their singularity and uncanny ability to adapt. But as important as these traits might be in a herd of elephants as they adapt to climate change or human encroachment, they are not always so desirable in the laboratory.
This is especially true when the cells are grown on a large scale for therapeutic purposes, an increasingly common occurrence as more cell-based research bridges the lab to the clinic. In this situation, variation is a four-letter word, and scientists expend immense effort and costs to ensure the millions of cells that are often required for a single dose are uniform and consistent. Cells require the right conditions, the right food, an environment free of contaminants, and a lot of attention. Until now, there has been no sure-fire way to precisely monitor a cell culture to know what the cells are doing or need, at any given moment, and one misstep can result in an entire culture going down the drain.
Shana Kelley, a professor in the Leslie Dan Faculty of Pharmacy at the University of Toronto, thinks she has a way to overcome this problem. With support from Medicine by Design, Kelley and her project team recently published a paper in Nature Chemistry where they describe an interface that converts biological information into electronic signals. This interface offers a new way to monitor cell cultures, making it possible to control them more precisely.
“Cell-based therapies are fairly new, and developing ways to make the cultures as efficient as possible is an area that’s only recently gathered attention, so it’s a wide-open field,” Kelley says. “I think we’re ahead of the curve in terms of developing tools that are going to provide manufacturing facilities with a really powerful way to show that they have all of their quality measures under control.”
The team’s solution involves a merger between synthetic biology, chemistry and engineering. The goal is to create a sensor that can monitor the state of a cell culture and create a feedback loop for more efficient and cost-effective manufacturing. For example, the sensor could be integrated into a clean room — a manufacturing facility in which strict controls for air, temperature and light are maintained to reduce the number of airborne particles to close to zero — to allow a machine to measure and respond to cell culture activity without the need for human intervention, which increases the risk of contamination.
The sensor itself is a probe that works like those currently used to measure blood sugar in a patient with diabetes or the pH levels in a liquid, says Kelley.
Keith Pardee, an assistant professor at U of T’s Leslie Dan Faculty of Pharmacy, is the team’s synthetic biologist, tasked with creating the interface between the cells and the sensor itself. He’s had a hand at this kind of work before, having developed a low-cost and portable test for the Zika virus that provides rapid confirmation of the presence and strain of virus. As a next step, Pardee and Kelley are working toward creating new and faster diagnostics for influenza, thanks to a grant from the U.S. National Institutes of Health.
Pardee applied the same concept he used in these disease-diagnostics sensors — a gene circuit — to the cell interface project. However, instead of asking the sensor to provide a reading on a single output, such as whether a target gene is present or not, he set it up to provide measurements on several things at once.
“We wanted a system that could have multiple parallel sensors in the same culture. Using conventional gene circuit-based sensors, you can’t get more than three outputs because you start getting crosstalk between channels,” says Pardee. “So we’ve built these new sensors with electrochemical outputs that can operate in parallel. We have 10 now so, in theory, in a single droplet, you can ask 10 things that output to 10 different electrodes.”
This work could significantly expand the field of synthetic biology. Even in its nascent form, one can readily see the advantages of a system that can monitor ten, or perhaps hundreds of, different target genes at one time. An additional key feature of the interface is that it can be adapted to retrofit existing gene circuit-based sensors, making this new platform highly customizable. Moreover, this adaptability and multiplexing capacity has the potential to reduce monitoring costs to a fraction of what they currently are. While the advantage of such a system is readily apparent in a cell manufacturing setting, it could also be applied to health and agriculture, as a method to scan for antibiotic resistance genes, for example.
“I think, increasingly, as therapeutic cells in general become a mainstream modality of treatment, the requirements are going to go way up in terms of what you need to be doing to show that your batches of cells are ready for deployment into humans,” Kelley says.
“At some point, cell manufacturing is going to have to see increased automation to match the scale-up needs of regenerative medicine,” notes Pardee. “Right now it’s so labour-intensive and these cultures can be worth thousands of dollars, so you can imagine the implications if a batch goes sideways. It happens fairly often at this point so hopefully we can one day take the guesswork out of that method.”
The ability to finely monitor and tune also throws open a door to the creation of newer, more cost-efficient, cell therapies for a range of different kinds of diseases with high levels of complexity, such as cancer, which is one of the targets Kelley and her team are considering. If all goes well, their work will herald a future in which affordable, personalized cell therapies can be made in facilities across the globe.
This project is one of 19 team projects Medicine by Design funded in its first round through 2019 as part of its mandate to accelerate regenerative medicine breakthroughs and translate them into new treatments for common diseases. This article first appeared on Medium and was reprinted with permission of the author. (https://medium.com/@willemsela/toronto-team-tackling-unmet-need-in-cell-manufacturing-using-synthetic-biology-f3a8e7a204e0)
Lisa Willemse
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