Could synthetic biology solutions fix supply chain challenges?

Ask experts focused on the pharmaceutical supply chain their thoughts on the current state of the industry, and they are likely to express any number of concerns. From shortages of ingredients and finished product to vulnerabilities exposed by phenomena like the COVID-19 pandemic and severe weather events, there’s a widespread belief that change and innovation are much needed.

Christina Smolke, CEO of Antheia and Stanford University professor, recently shared her perspective on pervasive problems with the pharma supply chain, as well as innovative solutions like her firm’s plant-inspired medicine technology.

OSP: Could you please talk about the percentage of pharmaceutical products that rely upon crops and biological material for their formulation?​

CS: Nearly half of all pharmaceuticals, including many common and essential drugs, are sourced from nature. Plant-based drugs are used for a wide variety of indications, and are frequently used as analgesics, antitussives, chemotherapeutic agents, and neurotransmitter inhibitors.

OSP: What challenges do plant-reliant therapies face in production, sourcing, environmental impact, etc?​

CS: Because plant-based drugs are extracted from medicinal crops, they’re vulnerable to any disruption that affects crop health – that includes natural disasters (like the 2019-2020 wildfires in Australia), climate change, pests, and disease. These crops often can only grow under specific climate conditions, and can only be found in specific regions of the world.

Additionally, the process of extracting active pharmaceutical compounds from plants farmed as crops is an inefficient, expensive, and risk-laden process. While the technology required to transform these natural materials into medicines varies considerably, plant-based drugs are generally manufactured through a multi-step process that begins on specialized farms, where the medicinal crops are farmed and harvested. Once these plants arrive at processing facilities, they undergo extensive physical and chemical treatment to extract and isolate their medically relevant components.

Once isolated, these components are further modified through chemical reactions to become active pharmaceutical ingredients (APIs), the base of all drugs. This entire process often takes two to five years and is an extremely inefficient use of farming resources given the miniscule amount of active ingredients extracted from the overall plant biomass.

While nature is a powerful source of medicine, it is risky to rely on plants as raw materials as we currently do, because the supply of medicinal crops is so tied to variables outside of our control. At Antheia, we’re using synthetic biology to produce these highly complex medicinal molecules on demand, without the need for plants at all.

OSP: Could you please share your perspective on how disruptive health and weather events like COVID-19, the Australian wildfires and other occurrences mess up the pharma supply chain?​

CS: The supply chain for drugs sourced from plants is highly fragile and outdated and is susceptible to major disruptions from unpredictable events like droughts or wildfires. Over the course of the last year, COVID-19-related drug shortages have further strained our already fragile pharma supply chains, which proved unable to respond to rapid changes in demand.

Additionally, because the supply chains are geographically concentrated and distributed in certain process steps when export/import break down during these events, supply chains break down as well. It’s been made painfully clear that we need a new, agile manufacturing and distribution process to prevent future medicine shortages, and that can be implemented wherever they’re needed most.

OSP: Shortages of active ingredients are not exactly an uncommon problem in the pharmaceutical industry. Can you share your perspective on solutions the industry tends to lean on to prevent or mitigate shortages (i.e. stockpiling), and how effective or ineffective they might be?​

CS: Stockpiling is a necessary, but insufficient, disaster response strategy, and its challenges are well known – drugs can expire, it’s expensive to stockpile huge quantities of medicines, and some drugs cannot be effectively stockpiled at all. Stockpiling lacks the responsiveness and agility we need in a crisis.

The policies of the Strategic National Stockpile are currently under audit given its failure to prevent essential drug shortages in our time of crisis. We should complement stockpiling with a variety of other approaches – such as on-demand manufacturing – to build more resilience into the system overall.

Now is an opportunity to re-envision the program, recognizing that on-demand manufacturing technologies that can produce essential drugs in weeks, not months or years, is a complementary approach that should be supported by all stakeholders including government, academia, and private industry.

OSP: Your company’s synthetic biology technology is fascinating—could you share a nutshell description of how you got started, how it works, and how you see the industry putting it to work in the near and/or distant future?​

CS: My team and I have spent the past two decades studying how plants synthesize complex pharmaceutical compounds and developing technologies for reconstructing these complicated biosynthesis processes in brewer’s yeast - a simple microorganism that humans have used for thousands of years to ferment food and beverage. We’ve now advanced this work to a point where it can be commercialized and used to improve drug manufacturing at scale.

For background, traditional synthetic biology methods can reconstruct relatively short and simple pathways – with five to six enzymes and relatively few chemical reactions – which limits the plant-derived medicines that can be explored and manufactured.

Antheia has developed a novel approach to whole-cell engineering which can efficiently assemble some of the most complex molecules known to humankind. Whole-cell engineering programs the entire cell– optimizing each enzyme’s activities, expression, processing, and distinct micro-biochemical environments while balancing their interactions as part of an integrated system.

Unlike other synbio methods, whole-cell engineering enables the orchestration of longer pathways with 20+ enzymes and exponentially more potential interactions, opening up access to an unprecedented complexity of chemical space. At Antheia, we’re enabling the production of plant-inspired drugs that would be impossible or highly inefficient to explore, make, and scale through conventional methods; we have pioneered a synthetic biology platform that is able to produce highly complex medicinal molecules on demand, using plants as inspiration, not as raw supplies.

OSP: The paper on your biosynthesis work as published in NATURE​ also is fascinating; could you share a little more detail about the potential applications for the synthesized tropane alkaloids, tell us what response has been like since it appeared in September, and what the next steps are for the technology?​

CS: The tropane alkaloids hyoscyamine and scopolamine are neurotransmitter inhibitors and are classified as essential medicines by the World Health Organization for their use in treating neuromuscular disorders such as Parkinson's, intestinal disorders, and other issues caused by muscle spasms. Currently, global supply of these medicinal tropane alkaloids relies on intensive cultivation of nightshade plants, as direct chemical synthesis of these medical compounds is not commercially viable.

In this paper, we demonstrated the first successful microbial biosynthesis of hyoscyamine and scopolamine. We are currently working to scale this production process to commercially relevant levels and volumes, expanding the platform to produce a richer diversity of tropane alkaloids, and working with a number of collaborators to explore applications in the coming years.

OSP: Do you have anything to add we didn’t touch upon?​

CS: While the pandemic has most recently exposed how broken our current process is for manufacturing plant-based pharmaceuticals, the fragility of pharma supply chains has been evident for years. Our ability to provide medicines when and where they’re needed has long been tied to events outside the medical community’s control, from natural disasters (e.g. wildfires) to geopolitical events (e.g. changes in international trade agreements).

We need a fundamentally new manufacturing and distribution process to successfully provide drugs when and where they’re needed most. While a lack of agile, domestic manufacturing capacity is at the core of recent medicine shortages, they’re also tied up with a lack of investment in improved drug manufacturing technologies for a wide range of essential medicines; these issues have been well elaborated – but they’ve become painfully evident as the death toll from the pandemic has continued to grow.

We need more investment in advanced manufacturing technologies of all sorts, including synthetic biology and biomanufacturing, to turn the drug supply chain into a nimble operation that can effectively provide medicines on-demand and at scale.