Imagine a cross between one of those multi-color retractable pens and an epi-pen. But instead of colors, the device would have different medications. Now combine this with a tiny, droplet-sized sweatshop full of obedient single-celled organisms genetically engineered to produce those medications, and you’ve got what a team from MIT just published in Nature Communications: A new project, with funding from DARPA, that has demonstrated the ability to synthesize multiple medications on-demand and as-needed using yeast. The discovery could soon revolutionize our ability to deliver medicine after natural disasters or to remote locations.
Let’s stick with the metaphor of an epi-pen. First, the user presses the actuator, which mixes a chemical trigger into a culture of engineered Pichia pastoris cells. Upon exposure to certain chemical triggers, the cells are programmed to produce a protein: in the report, the team used estrogen β-estradiol, which caused the cells to express recombinant human growth hormone (rHGH), and also methanol, which induced the same culture of yeast to make interferon. By controlling the concentration of the chemical trigger and the population of P. pastoris, the team demonstrated that they could make their device produce a dose of either interferon or rHGH on command. To switch between products, they just pushed another button on the microbioreactor, which flushes out the cell culture with clean, sterile fluid.
“…rapid and switchable production of two biologics from a single yeast strain as specified by the operator.” -Lu, Ram et al
Figure 6(a). The principal component of the microbioreactor is a polycarbonate – PDMS membrane – polycarbonate sandwiched chip with active microfluidic circuits that are equipped for pneumatic routing of reagents, precise peristaltic injection, growth chamber mixing and fluid extraction. Image and caption: Lu, Ram et al
It might not be immediately apparent why there’s an advantage to having to tote around bacteria, rather than just having a cartridge of whatever medication you need to deliver. But consider the case of immune reactions in the field. Snake and spider bites can be fatal without the right treatment. Antivenin is hysterically expensive, though, and it needs special storage conditions to last. This device can maintain the yeast at a temperature it likes, until called to produce the necessary substance fresh on demand.
Vaccines, too, are an application for the new device. Remember Balto? The Iditarod commemorates a heroic journey to bring diphtheria antitoxin to a remote Alaskan village in the depths of a legendary storm. We now have a diphtheria vaccine. Senior engineer Tim Lu explains that the device could be used to produce a vaccine to prevent a disease outbreak in a remote village. Think about what Doctors Without Borders could do if they had a steady supply of vaccines created by a milliliter-scale device like this. “Imagine you were on Mars or in a remote desert, without access to a full formulary, you could program the yeast to produce drugs on demand locally,” Lu said.
Point-of-care biomanufacturing employs engineered yeast and portable microbioreactors for on-demand drug production, such as in an ambulance. Credit: MIT
This project builds on prior art, also from MIT. The cells are held within a table-top microbioreactor which contains a microfluidic chip, itself originally developed by Rajeev Ram, a professor of electrical engineering at MIT, and his team, and then commercialized by Kevin Lee — an MIT graduate and co-author — through a spin-off company.
So far, the system has been prototyped. The researchers are now investigating the use of the system in combinatorial treatments, in which multiple therapeutics, such as antibodies, are used together. Combining multiple therapeutics in this way can be expensive if each product requires its own production line, Lu says. “But if you could engineer a single strain, or maybe even a consortia of strains that grow together, to manufacture combinations of biologics or antibodies, that could be a very powerful way of producing these drugs at a reasonable cost.”
(Images courtesy of MIT)