Historically, plants and medicinal herbs have been used for centuries as remedies for ailments such as the common cold, nausea and skin conditions, as well as to boost digestion and support the immune system. Following decades of research leveraging the diverse chemicals that plants produce allow for the development of new drugs to help treat serious diseases such as heart disease and cancer, neurological disorders and viral infections.
 
Antheia, a science and technology company, is developing next generation plant-inspired medicines using fermentation to produce complex active pharmaceutical ingredients (APIs) that have so far only been attainable via botanical sources. By creating a pathway to produce APIs with fermentation, Antheia aims to enable more resilient, sustainable supply chains for drugs and essential medicines. 
 
Applying synthetic biology, genomics, informatics, and fermentation, the company harnesses the most beneficial molecules from plants to create APIs in more controlled and economical ways. By disrupting the traditional agricultural-based supply chain, the company aims to create more equitable channels of distribution, while accelerating the discovery of new medicines. –KB 
 
Contract Pharma: What is the fermentation process?
 
Antheia: In nature, the fermentation process occurs when microbes like yeast or bacteria break down a sugar source for energy under certain conditions that lead to a byproduct, such as alcohol. Humankind harnessed this process millennia ago for brewing beer in what’s widely considered our first foray into biotechnology. 
 
Modern fermentation technology holds great potential beyond preserving and making foods thanks to advancements in synthetic biology. Industrial fermentation can be used to manufacture industrially, medically, and nutritionally important compounds anywhere in the world, as long as the technical challenges of engineering a commercially-viable strain and process are overcome. The fermentation process can be regulated and optimized for greater output by adjusting just a few key variables, including temperature, acidity, oxygen, and nutrition source or feedstock. All microbes have a preferred temperature range in which they grow most efficiently. They also require oxygen, carbon, and nitrogen sources to provide energy to the organism.
 
When combined with synthetic biology, fermentation can be used to grow products or even create an entirely new bio-based compound.
 
Contract Pharma: What is API fermentation?
 
Antheia: Currently, many of the active pharmaceutical ingredients (APIs) and key starting materials (KSMs) for medicine are sourced from plants. The molecules that make up these pharmaceutical compounds are too complex to reproduce chemically, so the industry still relies on agricultural sources in a process that is often unpredictable, fragile, and inefficient. 
 
Antheia is developing technologies to reconstruct these complicated biosynthetic processes through fermentation with brewer’s yeast. Fermentation plays an essential role from strain development to product development. During R&D, synthetic biologists may generate dozens or even hundreds of candidate strains that need to be evaluated for their potential growth and product profiles. Researchers screen these candidates at a small scale to identify those that require another round in the Design-Build-Test-Learn (DBTL) cycle and those that should progress to process development. Dozens of strains can be screened simultaneously using high-throughput screening to assess the growth profile and to assess whether the engineered microbe produces the compound of interest under the less-than-ideal conditions of commercial scale production. 
 
Contract Pharma: What applications/drug products are made by fermentation?
 
Antheia: Fermentation and synthetic biology technology has evolved dramatically, impacting many different industries where it can enable full-scale manufacturing of new and better products, including essential medicines like we’re doing at Antheia. Others are using this technology to produce agricultural solutions, more sustainable chemicals, or direct-to-consumer products like food and personal care. 
 
Fermentation has been used for decades to produce therapeutics. In the 1970s, diabetics were treated with insulin extracted from pig pancreas glands. This was extremely inefficient – a single pound of insulin required 23,500 animals. Manufacturers Eli Lilly needed 56 million animals per year to meet the growing demand in the U.S. alone, so they turned to Genentech for a synthetic insulin solution. The Genentech team not only managed to create synthetic human insulin – one that was better tolerated by patients than the pig-derived insulin – but they also found a way to manufacture it in commercially relevant quantities. Using E. coli bacteria as a microbial factory, they replaced the trainloads of pig pancreases previously required to meet the insulin demand for diabetes patients.
 
A similar story unfolded for antibiotics during the Golden Age of Antibiotics from the 1950s to the 1970s. While a plethora of natural antibiotics were discovered in bacteria and fungi, including penicillin and other clinically relevant classes such as macrolides and cephalosporins, their manufacture relied on optimizing fermentation processes as well as genetic manipulation to increase yields.
 
Contract Pharma: What biological and analytical advances enable modern fermentation processes to deliver safe and effective next-generation small-molecule APIs?
 
Antheia: Synthetic biology, also known as engineering biology or biodesign, uses the power of biology to make a product or even create an entirely new bio-based compound, and is the result of five decades of advancement in molecular biology, genome sequencing, and DNA synthesis. The field is interdisciplinary, leveraging tools and technologies from several fields including molecular biology, chemistry, and engineering in order to produce complex compounds at scale. 
 
Computational tools have become essential for today’s biological research, from identifying new protein targets to comparing gene variations. Vast databases of -omics data – collectively containing an organism’s known genes (genome), mRNA (transcriptome), and proteins (proteome) – now exist for thousands of organisms and microorganisms. By mining these databases, we can unveil a number of important factors, including the function of an enzyme or group of enzymes in a pathway, the conserved areas of genes likely necessary for their product’s functionality, and regions more amenable to mutation and engineering.
 
Automation is another valuable tool that increases throughput while reducing human error, ensuring that the scale of high-quality data needed for synthetic biology is attained. For example, specialized liquid handling robots are adept at consistently and accurately preparing hundreds of samples of chemical reagents, DNA, buffers, and even cell cultures simultaneously, compared to just dozens of samples by manual preparation. 
 
Contract Pharma: What are the benefits of fermentation?
 
Antheia: At this time, nearly half of pharmaceuticals, including many common and essential drugs, are sourced from nature. This means that the active pharmaceutical compounds we rely on are extracted from plants farmed as crops. Farming for medicinal ingredients can lead to environmental distress due to the heavy reliance on natural resources, including the land, water, and fertilizer required to grow the large number of crops – from which only a trace amount of the target molecule is extracted. Crop cultivation is also vulnerable to natural disasters, climate change, pests, and disease, making agricultural supply chains for medicine largely costly, inconsistent, and inflexible to sudden changes in demand. The consequences, which include shortages of life-saving drugs, can be deadly. 
 
Shifting the plant-based drug supply chain from farming to the fermentation tank provides quality control improvements that enable manufacturers to produce higher-quality compounds in a facility in just weeks, rather than years to grow, harvest and purify plant-based compounds. It also eliminates the negative environmental impacts of conventional industrial agriculture, monoculture or overharvesting practices, variability of growing conditions or harvest yield. Fermentation also enables an onshore manufacturing approach. Instead of relying on a complex multi-acre farm, possibly thousands of miles from the facility it needs to travel to, we can localize production for a more controllable and consistent supply chain. These biomanufacturing facilities can be established domestically, eliminating the incredible logistical challenges, cost, and environmental toll of shipping compounds around the world, shortening shipping times and saving billions in unneeded transit costs.