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Advanced Engineered Microbes Could Be the Solution to Drug Development Challenges
Microbes can be designed to manufacture and deliver drugs based on your body’s input, could this be “AI” for biotherapeutics?
TL/DR: What should you take away from this article?
Two major challenges to drug development — models and drug delivery dynamics — are largely driven by the complexity of the humans in which they are deployed. The biology of humans is not going to change any time soon so more sophisticated and dynamic methods of drug delivery are needed. Utilizing engineered microbes might just reduce costs by improving success rates through development and minimizing adverse events. It can also allow for more effective therapy by precisely and dynamically delivering its payload. For investors, mark this as a space to watch and perhaps fairly soon as a percentage in your portfolio. For drug developers not in this area, it would be interesting to learn what boxes need to be checked before you venture into this delivery model. For patients, drugs delivered by these little helpers are in the clinic, but, outside of probiotic approaches, not approved for prime time. Ask questions and let’s see where this goes.
Challenges in Drug Development
Drug development is expensive. It costs an estimated $1.3-$2.1 billion to develop a drug. (1) Meanwhile, 90% of these therapeutics fail on their way to market. As a result, approved drugs bear the weight of all their failed siblings, increasing costs throughout the healthcare system. 400 years ago, alchemist and physician Paracelsus said: “All substances are poisons; there is none that is not a poison. The right dose differentiates a poison from a remedy.” (2) He was only half right. Approved therapies combat diseases and other conditions, but they can also cause adverse reactions that need to be treated. In some cases, these reactions arise because the therapy hits unintended targets. These adverse drug reactions cost an estimated additional $39 billion annually partially because of drug-related hospital admission, prolongation of hospital stay, and emergency department visits. (3)
It’s not controversial to say that drug development is full of challenges. Two of these challenges — human complexity, and drug delivery dynamics — are particularly ripe for disruption. Engineered microbes can help tackle these challenges, and their use is closer than you might think.
The Model Conundrum: Drug Development Fails to Account for Human Complexity
Drugs are rigorously screened in development to hit well-designed milestones that predict later-stage success in humans, but failure rates remain stubbornly high. This is due in part to a model/complexity problem: our models used to develop therapies do not include local and systemic conditions found in humans.(4,5) We discover, design, and optimize our therapeutics in test tubes, cell lines, and animals. We use these models to limit variables so we can draw proper conclusions and ensure safety. When finally brought to humans, the drug is delivered near the maximum tolerated dose everywhere, non-specifically. This introduces more variability and thus more complexity, increasing the chances that the drug hits unintended targets, which will alter conditions and thusly changes many of the parameters that we used to study the drug in the first place. Once in humans, the pharmacokinetics (the movement of drug into, through, and out of the body) change, and because it is a living system, the change is continuous. The challenge is therefore to control the dose and location of the drug once in humans.
No drug’s journey is the same for two different people. The half-life (time taken for the plasma or blood level of the drug to fall by half) is affected by the unique properties of the drug, but also by an individual’s age, genetics, concurrent medications, and existing conditions such as liver or kidney disease. Yet, drug durability and availability are challenges that can diminish the success of a drug candidate, particularly when it’s in humans. We are good at manipulating the properties of a drug but we design to a static, uniform environment and this will always limit our success.
Engineered Microbes: The Ultimate Drug Delivery Drivers (Who Also Happen to Live Inside You)
Given these challenges, it would be beneficial to have a drug delivery system that is targeted, durable, and locally tunable. Enter designed microbes. Many of our therapeutics today are manufactured using engineered microbes in so-called microbial cell factories. Yet, engineered microbes such as yeast or bacteria can also be designed to address these drug delivery challenges using Engineered Living Biotherapeutic Products (eLBP). There are several advantages to using such eLBPs.
First, many of these microbes already exist within us, living harmoniously through millions of years of co-evolution. They are often uniquely located within strategic drug deployment zones such as the GI tract, skin, oral cavity, respiratory tract, and genitourinary tract. Not only are there a host of diseases associated with these areas, but there are well-documented gut-brain, gut-liver, and gut-kidney axes linked with the microbiome in these locations, thereby extending the reach of these microbes.
Second, the technology exists to direct microbes to deliver specific “payloads” at specific amounts and frequencies. Given that these microbes could be designed to replicate, they can controllably maintain a variety of dosages, delivered for weeks to years. (6,7) Eventually, it is likely that these microbes could receive updated instructions, much like the over-the-air updates some cars receive today.
Third, these living organisms can be designed to deliver their drugs based on the conditions around them. For example, scientists at Harvard and MIT have designed yeast that can detect pathogenic inflammatory conditions in the gut and mitigate it.(8) In February 2023, two separate publications announced the design of microbial robots able to perform these functions (discussed further below).
Fourth, rather than delivering the drugs themselves, these microbes could be engineered to limit the negative effects of a drug. They can be designed to prevent the accumulation of traditionally delivered drugs in healthy areas of our body, helping to reduce secondary effects. Alternatively, they could be designed to interact with specific areas of the body to produce a unique set of conditions that cause a drug to have its intended effect. These microbes would be the equivalent to many adjuvant therapies given today. In a sort of proof of principle, an article recently announced the discovery of the microbial enzymes that inactivate an ulcerative colitis drug and predict subsequent treatment failure. (9)
Taken together, engineered microbes could be leveraged to provide the precision required to give more drug candidates better chances of success and to reduce adverse reactions. That might mean our library of failed but well-designed candidates is not a sunk cost after all. They could be reintroduced using engineered microbes providing a bolus of R&D activity upfront.
Beyond Limitations: Overcoming Challenges in Microbial Cell Factories and Drug Delivery, Today
This is not a novel idea. Microbial cell factories and eLBPs come with their own host of challenges. For example, microbes are thought to be able to produce only bulky recombinant proteins, thus limiting the addressable drug market. Recombinant proteins, or just proteins, are produced by living systems, such as microbes, and are generally larger and more specific than traditional small molecule drugs (e.g. aspirin). Small molecules are considered more “economically sustainable” and more accessible than protein-based therapies. (10) Recent advances dispel this limitation. Microbial cell factories are being designed to produce a whole range of small molecules and active compounds. (11, 12) One group engineered baker’s yeast to produce penicillin-g consisting of 23 atoms. (13) Genetic drift is also a challenge. There is no reason to believe these engineered bacteria will exist outside the laws of evolution. Their programming could be naturally marred over time, resulting in unwanted effects. Techniques are being developed to prevent or contain such scenarios.
Finally, many of the advances made in microbial cell factories do not directly convey to microbial therapeutics. This is because the synthetic biology tools used to design and optimize these microbes also require very controlled environments. Introducing the harsh pH environment of the gut can destroy these microbes. There has been significant advancement in developing delivery pathways and guidance systems. In fact, recent studies have demonstrated the use of micromagnets to guide eLBPs to desired locations. (14) Consider that both fields, microbial cell factories, and eLBPs, are rapidly growing and becoming more sophisticated. While one field is yielding microbes that are producing complex small molecules or even logic-gated proteins, the other is creating symbiotic human companions. There are many reasons to believe innovation in these spaces will overlap, reinforce each other, and overcome these challenges.
Groups are working in this space now, showing remarkable scientific and regulatory progress. (15) Companies such as Synlogic (SYBX; Phenylketonuria), Precigen Actobio (PGEN; Type 1 Diabetes), Vendanta (VBNCR; C. diff), and Seres (MCRB; Gastrointestinal infections, bacteremia, and graft versus host disease) have products in phase 2 and beyond. The eLBPs are non-systemic, reversible, easily administered, safe, and can work alone or in combination, all of which have likely helped its advancement to this stage of development. Ferring just received approval for Rebyota, a microbiota-based live biotherapeutic designed to combat C. diff infection. While not an eLBP, this does mark a milestone in the field. There are new entrants and venture capital is investing in early-stage companies in this space.(16) However, it is a new space and not on the same level as traditional small-molecule drug development. Still, a recent review highlighted the eye-opening degree to which the challenges are being overcome and delivery modalities perfected. (17) In the past month alone, two groups have published significant advances. One group from the East China University of Science and Technology published the development of an intelligent responsive bacteria for diagnosis and therapy (i-ROBOT) and its effect on inflammatory bowel disease (IBD). (18) Another group from the University of Chinese Academy of Sciences, built their own microbial robot called TBY-robot, which self-adapts and self-targets to find diseased sections within the GI tract. (19) The Wyss Institute also recently announced an adjuvant antibiotic. (20) Meanwhile, Synlogic’s Phenylketonuria (PKU) program is advancing through the regulatory process.
The spacing between advancements in this space is shortening and the impact on drug delivery is already in the clinic suggesting the use of eLBPs is arriving. If you trace the arc and consider its trajectory, safe and effective eLBPs, and their reusable mechanisms will be available for precise and tunable drug delivery in the near future. It stirs up markets and perhaps mind-disrupting questions:
- Will blockbuster drugs be replaced?
- Can these eLBPs become more sophisticated and coordinated, thereby creating a network that senses and responds to human health in real-time?
- What would the impact be on health equity if these were cheaply and widely distributed since they could be self-maintained?
- How would clinical trials and the role of the regulator need to adapt?
One final question, knowing that bacteria can be designed to coordinate activity based on electrical signals, what happens when Artificial Intelligence (AI) orchestrates these signals to maintain our microbial-based health system? This, too, is not a remote fantasy.
Sources:
1) Tufts Center for the Study of Drug Development
2) Paracelsus (1493–1541) — Science Learning Hub
3) Sultana, Janet, Paola Cutroneo, and Gianluca Trifirò. “Clinical and economic burden of adverse drug reactions.” Journal of Pharmacology and Pharmacotherapeutics 4.1_suppl (2013): S73-S77.
4) Ingber, Donald E. “Human organs-on-chips for disease modelling, drug development and personalized medicine.” Nature Reviews Genetics 23.8 (2022): 467–491.
5)Singh, Vijay K., and Thomas M. Seed. “How necessary are animal models for modern drug discovery?.” Expert opinion on drug discovery 16.12 (2021): 1391–1397.
6) Heavey, Mairead K., et al. “Discovery and delivery strategies for engineered live biotherapeutic products.” Trends in Biotechnology 40.3 (2022): 354–369. https://www.sciencedirect.com/science/article/abs/pii/S0167779921001761
7) Yi, Xu, et al. “The Host Microbe Interface: A Systems Biology Approach.” Cell Host & Microbe, vol. 24, no. 2, 2023, pp. 159–173., doi:10.1016/j.chom.2023.01.008.
8) Scott, Benjamin M., et al. “Self-tunable engineered yeast probiotics for the treatment of inflammatory bowel disease.” Nature medicine 27.7 (2021): 1212–1222. https://www.nature.com/articles/s41591-021-01390-x
9) Macpherson, Andrew J., and Uwe Sauer. “Secrets of microbiota drug metabolism.” Nature Medicine (2023): 1–2.
10) Makurvet, Favour Danladi. “Biologics vs. small molecules: Drug costs and patient access.” Medicine in Drug Discovery 9 (2021): 100075. https://www.sciencedirect.com/science/article/pii/S2590098620300622
11) Zhou, Yuxi, and Yong Han. “Engineered Bacteria as Drug Delivery Vehicles: Principles and Prospects.” Engineering Microbiology (2022): 100034.
12) Sachin, Kumar, and Santosh Kumar Karn. “Microbial fabricated nanosystems: Applications in drug delivery and targeting.” Frontiers in Chemistry 9 (2021): 617353. https://www.frontiersin.org/articles/10.3389/fchem.2021.617353/full
13) Awan, A.R., et al. “Biosynthesis of the Antibiotic Nonribosomal Peptide Penicillin in Baker’s Yeast.” Nature Communications, vol. 8, 2017, pp. 1–8.
14) Heavey, Mairead K., et al. “Discovery and delivery strategies for engineered live biotherapeutic products.” Trends in Biotechnology 40.3 (2022): 354–369. https://www.sciencedirect.com/science/article/abs/pii/S0167779921001761
15) Sachin, Kumar, and Santosh Kumar Karn. “Microbial fabricated nanosystems: Applications in drug delivery and targeting.” Frontiers in Chemistry 9 (2021): 617353. https://www.frontiersin.org/articles/10.3389/fchem.2021.617353/full
16) Novome Biotechnologies. “Novome Biotechnologies Raises $43.5 Million Series B Financing to Advance its Pipeline of Therapeutically Engineered Microbes.” GlobeNewswire, 13 Sept. 2022, https://www.globenewswire.com/news-release/2022/09/13/2514955/0/en/Novome-Biotechnologies-Raises-43-5-Million-Series-B-Financing-to-Advance-its-Pipeline-of-Therapeutically-Engineered-Microbes.html.
17) Heavey, Mairead K., et al. “Discovery and delivery strategies for engineered live biotherapeutic products.” Trends in Biotechnology 40.3 (2022): 354–369. https://www.sciencedirect.com/science/article/abs/pii/S0167779921001761
18) Zou, Zhen-Ping, et al. “Biomarker-responsive engineered probiotic diagnoses, records, and ameliorates inflammatory bowel disease in mice.” Cell Host & Microbe (2022). https://www.sciencedirect.com/science/article/abs/pii/S1931312822005765
19) https://www.science.org/doi/10.1126/sciadv.adc8978
20) Wyss Institute for Biologically Inspired Engineering at Harvard University. “Engineered Live Biotherapeutic Product (ELBP) to Protect the Microbiome from Antibiotics.” Wyss Institute, https://wyss.harvard.edu/technology/engineered-live-biotherapeutic-product-elbp-to-protect-the-microbiome-from-antibiotics/.
Andrew Ryscavage is the Managing Director of Brinton Bio. A [former] scientist, bio-strategist, and ad[venture]ist, he seeks to empower the bioeconomy through biotechnology and life science consulting.
