Researchers at MIT have developed a portable system that can produce biologic drugs on-demand, obviating the need for expensive centralized manufacturing and potentially enabling doctors working in remote or developing parts of the world to create biopharmaceuticals that may be otherwise inaccessible. The DARPA-funded work is described this week in the journal Nature Communications.
Biopharmaceuticals, or biologics, are pharmaceutical drugs produced from biological rather than chemical sources. They may consist of proteins, sugars, and-or nucleic acids, or they may involve entire living cells. Examples include most vaccines, antibody therapies, and viral gene therapies (where viruses are genetically manipulated to have some medical benefit). The earliest example is biosynthetic insulin, created in 1982 and sold under the name Humulin, crafted using recombinant DNA.
Creating and manufacturing biologics is, however, expensive, owing largely the complexity and time scales involved; the MIT study notes that biologics represent a key driver in escalating health-care expenditures. Deploying biologics in developing regions of the world, in battlefield scenarios, and in emergency situations is a formidable challenge with consequences for basic drug availability.
"Currently, manufacturing of biologic drugs in the biopharmaceutical industry relies heavily on large-scale fermentation batches that are frequently monitored offline, to ensure a robust process and consistent quality of product," the paper explains. "However, as personalized medicines, single-use technologies and the desire for global and decentralized access to biologics are becoming increasingly important, there is a growing need for rapid, flexible, scalable and portable biomanufacturing systems that can be monitored/controlled online for affordable, safe and consistent production of biologics."
The platform developed by the MIT group is based on two basic components. The first is a system engineered to kick out multiple therapeutic proteins in response to programmed (chemical) cues, while the second is a millimeter-scale microfluidics production platform for actually producing the biologic end product. The result is a microbioreactor that is so far able to produce near-single dose levels of human growth hormone and the antiviral interferon-α2b.
The platform is based on a programmable variety of yeast known as Pichia pastoris. When exposed to estrogen β-estradiol, the cells are engineered to spit out growth hormones, while methanol causes them to produce interferon. Because the yeast cells can be grown in very high densities on top of relatively simple and expensive carbon substrates, it's possible to achieve large protein yields.
Within the microbioreactor, yeast cells are confined to a microfluidic chip where they live within the tiniest amount of liquid—which delivers the chemical signals—surrounded on three-sides by an impermeable polycarbonate wall, and, on the fourth, by a gas-permeable membrane. The membrane is used to both "massage" the cell-containing liquid to ensure it remains homogeneously mixed and to pass oxygen in and carbon-dioxide out. To ensure the optimal environment for cell growth, the system constantly monitors oxygen levels, temperature, and pH within the chamber.
When it comes time to produce a new biogenic, the liquid surrounding the yeast cells is flushed out and filtered to ensure that no cells escape. New liquid containing the new signal is piped in and the yeast cells begin producing a new protein. This flushing process—particularly the retaining of old cells for reuse—has apparently been a difficulty in prior microbioreactor research.
Future work will focus on making combinatorial therapeutics, e.g. treatments in which multiple biogenics are used together. With each one requiring its own production line, this is currently an expensive proposition. "But if you could engineer a single strain," offers MIT bioengineer Tim Lu in a statement, "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."